Content uploaded by Ovidiu Vrancianu
Author content
All content in this area was uploaded by Ovidiu Vrancianu on Jun 17, 2024
Content may be subject to copyright.
Molecular pathways and targeted
therapies in head and neck
cancers pathogenesis
Marian Constantin
1,2
, Mariana Carmen Chifiriuc
2,3,4
*,
Coralia Bleotu
2,5
, Corneliu Ovidiu Vrancianu
2,3,6
,
Roxana-Elena Cristian
2,6,7
, Serban Vifor Bertesteanu
8
,
Raluca Grigore
8
and Gloria Bertesteanu
8
1
Department of Microbiology, Institute of Biology of Romanian Academy, Bucharest, Romania,
2
The
Research Institute of the University of Bucharest, ICUB, Bucharest, Romania,
3
Microbiology
Immunology Department, Faculty of Biology, University of Bucharest, Bucharest, Romania,
4
Romanian
Academy, Bucharest, Romania,
5
Cellular and Molecular Pathology Department, S¸tefan S. Nicolau
Institute of Virology, Bucharest, Romania,
6
DANUBIUS Department, National Institute of Research and
Development for Biological Sciences, Bucharest, Romania,
7
Department of Biochemistry and
Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania,
8
ENT, Head&
Neck Surgery Department, Carol Davila University of Medicine and Pharmacy, Coltea Clinical Hospital,
Bucharest, Romania
The substantial heterogeneity exhibited by head and neck cancer (HNC),
encompassing diverse cellular origins, anatomical locations, and etiological
contributors, combined with the prevalent late-stage diagnosis, poses
significant challenges for clinical management. Genomic sequencing
endeavors have revealed extensive alterations in key signaling pathways that
regulate cellular proliferation and survival. Initiatives to engineer therapies
targeting these dysregulated pathways are underway, with several candidate
molecules progressing to clinical evaluation phases, including FDA approval for
agents like the EGFR-targeting monoclonal antibody cetuximab for K-RAS wild-
type, EGFR-mutant HNSCC treatment. Non-coding RNAs (ncRNAs), owing to
their enhanced stability in biological fluids and their important roles in
intracellular and intercellular signaling within HNC contexts, are now
recognized as potent biomarkers for disease management, catalyzing further
refined diagnostic and therapeutic strategies, edging closer to the personalized
medicine desideratum. Enhanced comprehension of the genomic and
immunological landscapes characteristic of HNC is anticipated to facilitate a
more rigorous assessment of targeted therapies benefits and limitations,
optimize their clinical deployment, and foster innovative advancements in
treatment approaches. This review presents an update on the molecular
mechanisms and mutational spectrum of HNC driving the oncogenesis of
head and neck malignancies and explores their implications for advancing
diagnostic methodologies and precision therapeutics.
KEYWORDS
head and neck cancer, molecular pathways, targeted therapy, monoclonal antibodies,
genomic, epigenetic, ncRNA
Frontiers in Oncology frontiersin.org01
OPEN ACCESS
EDITED BY
Natalia Isaeva,
University of North Carolina at Chapel Hill,
United States
REVIEWED BY
John Morton,
University of Colorado Anschutz Medical
Campus, United States
Manu Prasad,
Memorial Sloan Kettering Cancer Center,
United States
*CORRESPONDENCE
Mariana Carmen Chifiriuc
carmen.chifiriuc@bio.unibuc.ro
RECEIVED 20 January 2024
ACCEPTED 03 June 2024
PUBLISHED 17 June 2024
CITATION
Constantin M, Chifiriuc MC, Bleotu C,
Vrancianu CO, Cristian R-E, Bertesteanu SV,
Grigore R and Bertesteanu G (2024)
Molecular pathways and targeted therapies in
head and neck cancers pathogenesis.
Front. Oncol. 14:1373821.
doi: 10.3389/fonc.2024.1373821
COPYRIGHT
©2024Constantin,Chifiriuc, Bleotu,
Vrancianu, Cristian, Bertesteanu, Grigore and
Bertesteanu. This is an open-access article
distributed under the terms of the Creative
Commons Attribution License (CC BY). The
use, distribution or reproduction in other
forums is permitted, provided the original
author(s) and the copyright owner(s) are
credited and that the original publication in
this journal is cited, in accordance with
accepted academic practice. No use,
distribution or reproduction is permitted
which does not comply with these terms.
TYPE Review
PUBLISHED 17 June 2024
DOI 10.3389/fonc.2024.1373821
1 Introduction
From the very heterogeneous group of head and neck cancers
(HNC) (1), the head and neck squamous cell carcinomas (HNSCC)
produced by the transformation of the squamous cell epithelia
lining the oral cavity, pharynx and larynx are the sixth most
common type of cancer (2–4), with 700,000 - 900,000 new cases
recorded annually (2,4), responsible for 0.5% (in case of
oropharynx cancers) to 1.9% (for lip and oral cavity cancers) of
deaths from all cancers combined (2).
The most invoked etiological factors are smoking, alcohol
consumption (5,6) and HPV (human papillomavirus) infections
(7a; 7b; 8–14). In addition, several factors contribute more or less to
HNC development, including EBV (Epstein-Barr virus) infections
(15,16), laryngopharyngeal reflux (17), chewing betel quid (Areca
nuts) (18,19), poor oral hygiene (20), oral dysbiosis (21), pro-
inflammatory diet (22,23), and inhalation of airborne pollutants
(24,25). With the development of molecular diagnostic techniques,
many genetic aberrations (4,26–28) and epigenetic factors (29)
have been revealed.
HNC presents significant challenges in terms of both diagnosis
and treatment. Late diagnosis due to the lack of effective screening
strategies often complicates treatment options and reduces overall
survival rates (30). The heterogeneous nature of HNC further adds
to the complexity, requiring tailored approaches for different
subtypes (24,31–34). Moreover, the aggressive nature of
traditional treatments like chemoradiotherapy can lead to
significant side effects and reduced quality of life for patients (35).
The choice of the appropriate therapeutic strategy must
consider the anatomical site, tumor stage, and etiological factors
and could include surgery, radiotherapy, chemotherapy,
immunotherapy, and, more recently, targeted therapies. Despite
the poor outcomes in the advanced stages (36), the latter is expected
to appropriately address the high heterogeneity of HNC.
Consequently, it will contribute to better patient outcomes and
improved 5-year survival rates, which currently average is around
50% (2,33,37).
Various clinical trials have been undertaken around the world
on patients with HNSCC. In the clinicaltrials.gov database, 1266
clinical studies with the condition/disease ‘HNSCC’have been
registered since 2022. Recently, Goel and collaborators
summarized the results of a large number of clinical trials
examining the efficacy of immunotherapy and molecular-targeted
treatments. A total of 393 studies were completed out of 1266 trials
registered, while 590 studies were still recruiting. Docetaxel,
cisplatin, and 5-fluorouracil (5-FU) have been identified as the
most often used medications in clinical trials worldwide (38), but
monoclonal antibody-based medicines such as nivolumab,
pembrolizumab, cetuximab, panitumumab, zalutumumab, and
nimotuzumab also hold significant promise for future therapeutic
applications (39–41). However, the poor prognosis for many HNC
patients and high rates of locoregional recurrence and metastasis
advocate for better screening methods, more effective and tolerable,
personalized treatment strategies (42). This paper reviews the
molecular mechanisms involved in HNC, summarizing the
signaling pathways harboring genetic aberrations (RAS–RAF–
MEK–ERK, PIK3–AKT–mTOR, WNT/beta-catenin, JAK-STAT,
NOTCH, and HIF–VEGF), epigenetic mechanisms and the roles
of ncRNAs and tumor microenvironment in neoplastic progression.
We also tried to summarize the therapies targeting the abnormal
functioning of these signaling pathways and their efficacy.
2 HNC molecular pathogenesis
The development of HNC is a multistep process in which
mutations are accumulating in the main cellular signaling
pathways that regulate proliferation, cell death, angiogenesis and
immune system functions (3)(Figure 1).
2.1 Cell cycle deregulation in HNSCC
The most affected cell cycle regulating genes in HNC are TP53,
RB,CCND1,CDKN2A/INK4,andCDK6, unblocking the G1/S
transition. Thus, TP53 protein function is impaired in 50–80% of
cases, the mutations in the TP53 gene in HNSCC being the seventh
most frequent in cancer diagnosis worldwide (43). Several types of
mutations (deletions, insertions, and frameshift mutations, and
point mutations) in the TP53 protein are associated with
increased risk of progression from mild dysplasia to invasive
carcinoma and unfavorable tumor progression (33,44–47).
Specifically, TP53 missense mutations in the DNA binding region
are significantly enriched in metastases and are associated with a
common fragile site in chromosome 11, leading to amplification
and overexpression of genes with established role in metastasis (45).
In HPV-positive HNC, TP53 mutations are sporadic, as the
function of this gene is selectively abrogated by viral proteins E6
and E7.
The RB1 gene function is altered by unilateral or bilateral
deletions, methylation of the RB1 promoter, or point
mutations (48).
The CCND1 gene is overexpressed in 30%-46% of cases, leading
to G1 phase shortening and rapid entry into the S phase, bypassing
the influence of growth factors and increasing the proliferation rate
of gene-defective cells. These alterations are reported in cancers
with frequent recurrence, lymph node metastasis, and reduced
survival rate (49,50).
After CCND1, the third most frequent alteration in HNC is the
potent inhibitor CDKN2A, a regulator of cyclin activity and
progression to S phase. CDKN2A alterations including deletions
(more common in HPV-negative tumors), hypermethylation, and,
less commonly, mutations in exon 2 (rarest in oropharyngeal
tumors) are associated with metastatic cancers with poor
prognosis (51). In laryngeal squamous cell carcinomas, mutations
in the CDKN2A gene occur in approximately 14% of cases (52).
CDK6 is overexpressed in some oral tumors and correlates with
tumor stage advancement and progression (36).
Constantin et al. 10.3389/fonc.2024.1373821
Frontiers in Oncology frontiersin.org02
2.2 DNA repair pathway
The DNA repair pathway is a mechanism by which cells in the
G1 or G2 phase are halted at checkpoints to identify and correct
errors in the nucleotide sequence of nuclear genetic material. This
process is initiated by the detection of DNA lesions and is activated
by the ATM (ataxia-telangiectasia mutated) and ATR (ataxia-
telangiectasia and Rad3 related) kinases, along with proteins such
as BRCA1, BRCA2, (Mediator of DNA Damage Checkpoint 1) and
T53BP1 (Tumor Protein P53 Binding Protein 1). Additionally, the
synthesis of PALB2 (partner and locator of BRCA2), which
interacts with BRCA1 and BRCA2, plays a crucial role in the
DNA repair process.
In HNC, the most mutated genes in this signaling pathway are
ATM (25%), BRCA2 (9.2%), BRCA1 (5.75%), and ATR (4.36%) (53–
56). Recent studies have revealed that the disrupted expression of
specific components within the DNA repair machinery, stemming
from mutations in key pathway genes like ATM and BRCA1, can
yield valuable prognostic insights for HNC patients (56,57).
The alterations in critical cellular signaling pathways governing
proliferation and cell survival have been exploited to create
customized treatments for HNC individuals. The increasing
interest in exploring the cell cycle (CDK4/6, CCND1, CDKN2A)
and the DNA repair pathways (BRCA, ATM, ATR) is demonstrated
by clinical trials (NCT03356223, NCT03065062, NCT03024489,
NCT05878964, NCT04576091, NCT04491942, NCT02567422)
actively investigating their potential in the broader context of
HNC such as CDK4/6 inhibitors for HPV-negative tumors (42).
2.3 RAS–RAF–MEK–ERK signaling pathway
Thispathwayinvolvesnumerousproteinsandreceives
biological signals from the extracellular space through various
ligand-receptor pairs, including TGFaand EGF–EGFR/ERBB1/
HER1, ERBB2/HER2, PDGF–PDGFRA and PDGFRB, IGF–
IGF1R, FITL–KIT/c-KIT, FLT3L–FLT3, HGF–MET, and FGF–
FGFR. These signals are transmitted into the nucleus, where they
activate genes involved in cell proliferation and differentiation,
inflammation, evasion of apoptosis, and support of angiogenesis
(58–63). Interaction with cytokine ligands activates transmembrane
receptors and recruits the growth factor receptor-bound protein 2
FIGURE 1
Main signaling pathways disregulated in HNC at the genomic or transcriptional level. Black arrow-ended lines indicate activation and red bar-ended
lines indicate inhibition. RAS–RAF–MEK–ERK (A, B) and PIK3–AKT–mTOR (C) signaling pathways are involved in promoting cell survival and
proliferation (D), antagonistically to the WNT pathway (E), in which AXN1/2 blocks beta-catenin activity. By enhancing JAK/STAT signaling (F), VEGF
proteins (G), the main angiogenic molecules, are activated. Alternatively, VEGF expression is also modulated by hypoxia-induced factor 1A (H).
Frequently reported in HNCs, angiogenesis builds the vasculature through which the tumors are supplied with oxygen and allows their progression
and a worse prognosis. On the other hand, the NOTCH signalling pathway is involved in cell growth and evasion of apoptosis (I). Very important in
the control of tumour processes in head and neck cancers is the Hippo pathway (J), which, when activated, phosphorylates YAP/TAZ, causing its
intracytoplasmic sequestration and degradation, preventing its translocation to the nucleus and activation of TEAD. TEAD activation leads to cell
proliferation. For further details, please see the text.
Constantin et al. 10.3389/fonc.2024.1373821
Frontiers in Oncology frontiersin.org03
(GRB2) adaptor protein, which interacts with SOS1 protein (the
human homolog of Drosophila son of sevenless 1). This is a RAS-
specific guanine nucleotide exchange factor and reacts with RAS
family members, the core proteins of this signaling pathway (64,
65). The RAS family of GTPases comprises three members, KRAS
(Kirsten RAS oncogene homolog), HRAS (Harvey RAS oncogene
homolog), and NRAS (Neuroblastoma RAS oncogene homolog),
which transmit the signals downstream to RAFs (from the
canonical RAS–RAF–MEK–ERK pathway), RALGDS (from
the RALGDS–RAL–PLD1 signaling pathway), RASSF1 (from the
RASSF1–MST1 signaling pathway) or PI3K (from the PI3K–AKT–
mTOR signaling pathway) (66,67). In the canonical RAS–RAF–
MEK–ERK pathway, RAS proteins are the first members of a four-
step cascade of cytoplasmic protein kinase kinases, which include:
(1) RAF (rapidly accelerated fibrosarcoma kinase), RAF1/c-RAF,
BRAF and ARAF family of kinases, designated MAPKKK or
MAP3K; (2) MEK (mitogen-activated protein kinases); (3) ERK
(extracellular signal-regulated kinase) (68,69). In the RAS–RAF–
MEK–ERK signaling pathway, overexpression of EGFR/ERBB1
occurs early in the progression of HNSCC, leading to poor
prognosis (70). In tumor xenografts of HPV-positive HNSCC, it
enhances the response to radiotherapy by decreasing the expression
of the HPV protease E6 and affecting DNA repair mechanisms (71).
In most HNC, members of the RAS gene family are most
frequently mutated, followed at a long distance by those of the
RAF gene family (72). In a study of 51 patients with HNSCC
(with higher prevalence in the larynx and trachea area),
mutations of the KRAS gene (sometimes designated KRAS1 or
KRAS2) were detected in 35% of cases, and mutations of the
HRAS gene in 33% of cases, with the caveat that KRAS mutations,
HRAS mutations, and HPV infection are mutually exclusive (68).
The most frequent mutations (7%) occur in the HRAS gene
(mainly in the oral cavity and salivary gland tumors and
associated with advanced stages of tumors), with the other two
family members, KRAS, at 2.89% (mostly in syn-nasal tumors and
often associated with HPV infection), and NRAS, at 2.20%
(predominantly in nasopharyngeal tumors) (69). Members of
the RAF gene family undergo fewer mutations (in about 3% of
cases) compared to RAS genes, with the most known mutations
reported in the BRAF gene (V599/600E, G468/469A, and Q257R)
(58). In HNC, 6% of cases have heterozygous mutations in exons
12 and 13. Because KRAS activates only the wild-type BRAF gene,
mutations in KRAS and BRAF genes never occur together in HNC
and are redundant (58).
Many inhibitors targeting this pathway have been developed,
essentially modifying the therapeutic strategy of cancers. Starting
from compound 12,first reported by the Schokat group in 2013 (73),
a series of inhibitors based on the compound 12 structure are
developed, such as ARS-853 and ARS-1620 (74,75). The
KRASG12C-specificdrug,AMG510 (storasib),firstwentinto
clinical trial in 2019 and was subsequently proven by the FDA in
2021 (76,77)(Table 1).
TABLE 1 Clinical trials for HCN targeted therapies.
No. Drug Mechanism
of action Disease Outcomes/
Expected results
Patients
enrolled Year Clinical
trials References
1 Storasib KRAS
G12C
inhibitor
Metastatic
NSCLC
Potential effective first-line therapy
for subgroups of NSCLC patients
42 2022 NCT04933695 77
2 Dacomitinib EGFR inhibitor (EGFR)-driven
advanced
solid tumors
Progression free survival, duration
of response
104 2021 NCT04946968 –
3 Vandetanib antineoplastic
kinase inhibitor
Precancerous
head and
neck lesions
Effect of vandetanib compared to
placebo on microvessel density
20 2012 NCT01414426 Awaiting
for results
4 Panitumumab human
monoclonal
antibody
against EGFR
Unresected
LA-HNSCC
Panitumumab cannot replace
cisplatin in the unresected stage III-
ivb HNSCC treatment
152 2012 NCT00547157 78
5 Panitumumab human
monoclonal
antibody
against EGFR
LA-HNSCC Panitumumab did not durably
improve quality of life swallowing
as compared with standard
with cisplatin
320 2017 NCT00820248 79
6Gefitinib tyrosine
kinase inhibitor
Advanced-stage
or
recurrent HNC
Gefitinib had marginally better
results in terms of overall response
and safety as compared
to methotrexate
200 2021 –80
7 Erlotinib EGFR inhibitor Hnscc Feasible and safe therapeutic option 35 2022 NCT: CTRI/
2020/
02/023378
81
(Continued)
Constantin et al. 10.3389/fonc.2024.1373821
Frontiers in Oncology frontiersin.org04
Another KRASG12C-specific covalent inhibitor, MRTX849
(adagrasib), developed by the Mirati group, also went into clinical
trial in 2019 (92). Cetuximab is a chimeric mouse-human
monoclonal IgG1 antibody against the extracellular domain of
EGFR that can inhibit the functions of EGFR and induce cancer
cell death via antibody-dependent NK cell-mediated cytotoxicity
(93). In 2006, FDA approved the combination of cetuximab with
radiotherapy for the treatment of locally advanced (LA) - HNSCC
(94). In a study published in 2023, the conjugate of cetuximab with
IRdye700DX, which is activated by illumination at 690 nm, has
been used successfully on near infrared photoimmunotherapy to a
patient with local recurrence of nasopharyngeal squamous cell
carcinoma (95). Cetuximab, received full FDA approval for the
treatment of patients with K-RAS wild-type, EGFR-mutant HNSCC
following reports that its addition to radiation therapy results in
significant improvements in disease control and overall survival (96,
97). Other inhibitors of EGFR/ERBB1 tested for HNC treatment are
dacomitinib and vandetanib. When used with radiotherapy,
dacomitinib reduces tumor volume in HNSCC, while vandetanib,
and cisplatin radiosensitizes tumor cells. Combining vandetanib
with radiotherapy is more efficient than other monotherapies or
combination therapies (98,99).
TABLE 1 Continued
No. Drug Mechanism
of action Disease Outcomes/
Expected results
Patients
enrolled Year Clinical
trials References
8 Afatinib
and
pembrolizumab
irreversible EGFR
tyrosine
kinase inhibitor
Platinum-
refractory,
recurrent, or
metastatic
HNSCC
Afatinib may augment
pembrolizumab therapy and
improve the ORR in patients
with HNSCC
29 2022 NCT03695510 82
9 Everolimus and
carboplatin-
paclitaxel
mTOR inhibitor La t3–4/n0
3 hnscc
Safe, major tumor responses,
impacting tumor microenvironment
49 2013 NCT01333085 83
10 Taselisib PI3K
pathway
suppression
Metastatic
solid tumors
Favorable safety profile and early
signs of promising activity
34 2017 –84
11 Alpelisib PI3K
pathway
inhibitor
Hpv-
associated hnscc
Safety and preliminary
efficacy evaluation
9 2022 NCT03601507 Awaiting
for results
12 Alpelisib PI3K
pathway
inhibitor
Recurrent/
metastatic
HNSCC
Assesing early antitumor activity 40 2024 NCT04997902 Awaiting
for results
13 Buparlisib class I
PI3K inhibitor
Recurrent/
metastatic
HNSCC
Significant promise as a
treatment strategy
53 2014 NCT01527877 85
14 WNT974 WNT- porcupine
enzyme inhibitor
Advanced
solid tumors
WNT974 influence immune cell
recruitment to tumours; enhance
checkpoint inhibitor activity
94 2024 NCT01351103 86
15 Ruxolitinib clinical JAK1/
2 inhibitor
Operable
HNSCC
Anti-cancer effects 16 2023 NCT03153982 87
16 Pembrolizumab
combined with
tacitinib/
parsaclisib
Janus kinase
1 inhibitor
Advanced
solid tumors
Modest clinical activity; little effect
on T-cell infiltration in the tumor
159 2020 NCT02646748 88
17 Crenigacestat
(LY3039478)
Notch inhibitor Advanced or
metastatic
solid tumors
Poorly tolerated; lowered dosing
and disappointing clinical activity
94 2020 NCT02784795 89
18 Cetuximab
plus
bevacizumab
EGFR and VEGF
monoclonal
antibodies
HNSCC Significant reduction in
tumor vascularization
48 2012 NCT00409565 90
19 Bevacizumab VEGF
monoclonal
antibody
Recurrent or
metastatic
solid tumors
Improved the response rate and
progression-free survival with
increased toxicities
403 2025 NCT00588770 91
20 IK-930 Oral TEAD
Inhibitor
Targeting the
Hippo Pathway
Advanced
solid tumors
Evaluation of the safety, tolerability,
pharmacokinetics,
pharmacodynamics, and
preliminary antitumor activity
198 2025 NCT05228015 –
Constantin et al. 10.3389/fonc.2024.1373821
Frontiers in Oncology frontiersin.org05
Several monoclonal antibodies of EGFR are still under intensive
investigation, including panitumumab,nimotuzumab,and
zalutumumab. According to the results from CONCERT-2 and
HN.6 trials, panitumumab cannot replace cisplatin when combined
with radiotherapy for LA-HNSCC (78,79). In addition, combining
panitumumab with the standard chemoradiotherapy strategy failed
to provide any benefit(100). Adding nimotuzumab to radiotherapy
with or without cisplatin provided long-term survival benefits for
up to five years and improved the complete response rate in LA-
HNSCC patients (101). In a phase 3 clinical trial involving 536 LA-
HNSCC patients, nimotuzumab plus cisplatin and radiotherapy
significantly improved the locoregional control rate without
negatively impacting the quality of life (102). The promising
results strongly supported the addition of nimotuzumab to LA-
HNSCC patients who are treated with cisplatin and radiotherapy.
Another monoclonal antibody, zalutumumab, extended the survival
time from 8.4 to 9.9 weeks in recurrent or metastatic (R/M) HNSCC
patients who had failed platinum-based chemotherapy (103).
Meanwhile, moderate-to-severe skin rash during zalutumumab
treatment was related to superior OS, independent of HPV
infection and p16 status (104).
Some small molecular inhibitors of EGFR are also under
investigation for the management of HNSCC, including selective
inhibitors (e.g., gefitinib, erlotinib) (80,81,105,106) and dual-
target inhibitors (e.g., afatinib, lapatinib, and dacomitinib)
(82,107).
2.4 PIK3–AKT–mTOR signaling pathway
The PIK3–AKT–mTOR signaling pathway is very complex,
being activated by extracellular signals represented by hormones,
cytokines, and growth factors via receptors common with those of
the RAS–RAF–MEK–ERK signaling pathway or via the enzyme
PI3K (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase), directly or
indirectly, after PI3K activation by the GRB2, SOS, and RAS. This
pathway is involved in cell growth, differentiation, survival,
migration and proliferation, apoptosis evasion, and glucose
metabolism (108). The central actor of this signaling pathway is
the class I PI3K enzyme, which is part of the PI3K family of lipid
and protein kinases, classified into three classes (I, II, and III). The
class I enzymes function as secondary messengers in the
intracellular transduction of biological signals and are more
commonly associated with cancer (109,110). The PI3K signals
are transmitted through a phosphorylation cascade, represented by
PIP2 (phosphatidylinositol-4,5-bisphosphate), which becomes PIP3
(phosphatidylinositol-3,4,5-trisphosphate), AKT/PKB (Serine/
Threonine Kinase), and mTOR–RICTOR (Mechanistic Target Of
Rapamycin Kinase–Rapamycin Insensitive Companion of mTOR)
complex. Phosphorylation of AKT/PKB is antagonized by PTEN
(phosphatase and tensin homolog) activity, which
dephosphorylates the latter (111) and functions as an essential
tumor suppressor (112). Subsequently, the phosphorylated AKT/
PKB activates multiple downstream targets, promoting cell survival,
activating anti-apoptotic pathways, and blocking apoptotic ones.
PI3K and AKT can induce chromosome instability MET-
dependently, an event suppressed by PI3K/mTOR inhibition,
AKT depletion or PTEN overexpression (113). Interacting with
HGF (Hepatocyte Growth Factor), MET can activate the PI3K–
AKT–mTOR signaling pathway in endosomes independently of
EGFR (114) or in the presence of TP53 mutants, as is mainly the
case in patients with HPV-positive tumors (115). The MET gene is
overexpressed in over 75% of HNSCC and has an increased copy
number of 13%, associated with tumor progression and tumor
dissemination in the early stages (116). Mutations of the MET gene
are reported less frequently, but they seem to be involved in lymph
node metastasis (117,118). HNC may also carry somatic mutations
in PIK3R1 (~7%) and PTEN genes (51,119), with loss of function in
approximately 30% of HNC (more common than other cancers)
due to mutations, loss of heterozygosity in the 10q region (which
includes PTEN), detected in more than 70% of HNSCC, or
hypermethylation, reported in ∼5% of these. In addition, TSC1/2
and LKB1 genes could be inactivated by loss of heterozygosity
(TSC1/2), methylation (TSC2) and somatic mutations (LKB1)
(119)(Figure 2).
Although Akt is recognized as a key player in cell migration and
metastasis, its role remains controversial. Akt1 promotes cell
migration in fibroblasts but inhibits it in breast cancer, while
Akt2 has the opposite effects. The deletion of Akt isoforms can
impact cancer progression differently depending on whether it is
systematic or cell-autonomous (120,121). Akt regulates cell
migration through various mechanisms, such as phosphorylating
PAK1, Girdin/APE, and ACAP1, which are involved in cytoskeletal
dynamics and integrin trafficking, crucial for cell motility (122,
123). Further research is needed to fully understand these
phosphorylation events and their implications in cancer metastasis.
Currently, drugs that target PI3K for NOTCH1-mutant tumors
(124) or mTOR are undergoing clinical trials. Everolimus (RAD001),
an allosterically inhibitor of only mTORC1 but not of mTORC2, is
clinically used to treat various cancers, including previously treated
recurrent or metastatic HNSCC (38,83). BKM120, an oral, highly
specific pan-Class I PI3K inhibitor, has strong antiproliferative
characteristics in tumor cell lines (125). Previous studies with the
PI3Kainhibitors taselisib,TAK-117,andalpelisib in patients with
solid tumors have reported promising clinical results (84,126).
Taselisib treatment showed an overall rate response (ORR) of 36%
in patients with PIK3CA mutations but 0% in patients without
PIK3CA mutations (84). The phase I trial with alpelisib specifically
enrolled patients with PIK3CA mutations and showed an ORR of 6%
and a stable disease rate of 52% (127,128). Two phase II clinical trials,
including to date 47 patients, are currently evaluating the
clinical efficacy of alpelisib as monotherapy in HPV-positive
HNSCC (NCT03601507) and alpelisib in combination with the
farnesyltransferase inhibitor tipifarnib in HRAS- and PIK3CA-
mutant HNSCC (NCT04997902; 129). Buparlisib (BKM120),
another pan-PI3K inhibitor, exhibited limited antitumor activity in
patients with HNSCC, with a disease control rate of 49% and an ORR
of only 3% (NCT01527877; NCT01737450) (85,130). Another phase
II trial, including patients with HNSCC, revealed a modestly longer
median in patients receiving a combination of buparlisib and
paclitaxel than in the paclitaxel and placebo group (NCT01852292)
(131). The buparlisib/paclitaxel combination is currently in phase III
Constantin et al. 10.3389/fonc.2024.1373821
Frontiers in Oncology frontiersin.org06
trial in patients with HNSCC (NCT04338399). Understanding the
intricate interplay between Akt, Rho GTPases, and their downstream
effectors, such as PAK1, aswell as the regulatory networks controlling
RhoA expression, is essential for uncovering novel therapeutic targets
and strategies for combating metastatic cancer.
2.5 WNT/beta-catenin signaling pathway
The WNT(Wingless-Type)/beta-catenin signaling pathway is an
alternative to the PIK3–AKT–mTOR pathway for promoting cell
proliferation and avoiding apoptosis that includes three main
pathways, the canonical WNT/b-catenin signaling pathway and
the WNT/Ca2C and WNT/PCP non-canonical pathways (132–
134). They also promote dysplastic transformation [WNT3, in oral
leukoplakia (135), deterioration in histological grade, progression of
clinical stage, and heightened metastatic potential in cervical lymph
nodes [WNT3A, in laryngeal squamous cell carcinoma (136)],
amplification of migration and invasiveness [WNT5A (137) and
WNT5B (138), in OSCC], tumorigenesis and metastasis [WNT5A,
in nasopharyngeal carcinoma (139) and laryngeal squamous cell
carcinoma (137)],migration[WNT7A,inOSCC(140)],
proliferation and invasiveness [WNT7B, in OSCC (141)], cell
growth and survival and inhibition of apoptosis [WNT10B, in
HNSCC (142)]. In some OSCC, WNT11 is involved in tumor
suppression (143). Defects in the WNT11 gene are found in 5% of
OSCC, consisting of duplications, deep deletions or punctiform
mutations affecting its tumor suppressor function. Other WNT
genes are affected in smaller proportions (144).
Porcupine (Porc) is a membrane-bound O-acyltransferase
(MBOAT) by whose Wnt ligands palmitoylation takes place, a
process allowing them to be further secreted and recognized (145,
146). Therefore, repressing Porc can be a promising solution against
tumors with aberrant Wnt/b-catenin activation (147). WNT974 is a
potent, selective, and orally bioavailable first-in-class inhibitor of
Porcupine with preclinical activity in Wnt-dependent HNC (86).
Recently, Rodon and collaborators conducted a phase 1 study
(NCT01351103) to investigate the safety and efficacy of the
WNT974 in patients with solid tumors. The results of this clinical
trial revealed that this inhibitor could be tolerated and may
influence immune cell recruitment to tumors and enhance
checkpoint inhibitor activity (86). In a phase I clinical trial, OMP-
18R5 (vantictumab), a monoclonal antibody targeting FZD
receptors, inhibited tumor growth in HNC (148). In a phase Ib
clinical trial, 54 patients with locally recurrent or metastatic HER2-
negative breast cancer who were treated with weekly paclitaxel in
combination with escalating doses of vantictumab were enrolled.
The combination of vantictumab and paclitaxel was generally well
tolerated and had promising efficacy. However, the incidence of
fractures limits future clinical development of this particular WNT
inhibitor in metastatic breast cancer (149). XAV939, a tankyrase
inhibitor, inhibited b-catenin signaling attenuated cancer stem cells
progression, consequently eliminating the chemical resistance in
HNSCC (60,150).
2.6 JAK–STAT signaling pathway
The JAK–STAT signaling pathway is involved in diverse
physiological processes such as hematopoetic cell responses to
cytokines (151), cell growth, proliferation and differentiation,
survival, angiogenesis, and inflammatory or immune responses,
but also in pathological conditions like tumor processes (152–154).
The main proteins are JAKs (Janus kinases, named after the Roman
god Janus, known to have two faces), with for members (JAK1,
JAK2, JAK3 and TYK2, tyrosine kinase 2), and STAT (signal
transducer and activator of transcription), with seven members
(STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6)
FIGURE 2
Carcinogenesis in HNC from normal mucinous stage to invasive carcinoma stage, highlighting each stage, chromosomal regions affected by loss of
heterozygosity and genes that may be defective.
Constantin et al. 10.3389/fonc.2024.1373821
Frontiers in Oncology frontiersin.org07
(155). The JAK–STAT signaling pathway is activated in many
cancers, including HNC, mainly through overexpression of
STAT1, STAT3, and STAT5, with the first correlating with
favorable outcomes and the latter two with unfavorable outcomes
(33,156). In OSCC, overexpression of STAT3 and its accumulation
in the nucleus is associated with reduced survival or favorable
prognosis (157), promoting tumor angiogenesis by stabilizing and
modulating the activity of HIF1 (hypoxia-inducible factor 1), which
promotes the synthesis of VEGFs (158), a key protein involved in
tumor invasiveness and metastasis. However, in breast cancers and
some colorectal, spine, head, and neck cancers, activation of the
JAK–STAT signaling pathway appears to result in a more favorable
prognosis (159).
Several studies in human tumors and HNC cell lines have
identified the JAK/STAT signaling pathway as a potential
therapeutic target (160,161). The group of Kowshik
demonstrated that astaxanthin could hinder tumor progression by
attenuating JAK/STAT signaling and its target molecules, including
VEGF, cyclin D1, and MMP in the HPV-induced tumor models
(162). The JAK1/2-selective inhibitor ruxolitinib is FDA-approved
for several diseases, including myelofibrosis and graft versus host
disease (163,164). Currently, two multicenter, phase 1b clinical
trials are undergoing to investigate the safety and efficacy of
ruxolitinib (NCT03153982) and pembrolizumab (NCT02646748)
in patients with HNC.
2.7 NOTCH signaling pathway
The NOTCH signaling pathway is activated by two families of
ligands, Jagged (JAG1 and JAG2) and Delta-like (DLL1, DLL3 and
DLL4). Upon interaction with NOTCH receptors (NOTCH1,
NOTCH2, NOTCH3, and NOTCH4) they influence cell self-
renewal capacity, cell cycle exit, survival, proliferation, and
angiogenesis in a cell- and biological context-dependent manner
(165–167). NOTCH1 signaling suppresses tumor development by
promoting terminal keratinocyte differentiation and is probably
protective in advanced stages of HPV-induced carcinogenesis, by
reducing transcription of viral E6 and E7 genes (168). Conversely,
NOTCH signaling causes FGF1-mediated tumor invasiveness in
OSCC and increases mortality (167), probably through activation of
MDM2, which ubiquitinates TP53 and primes it for degradation
(169,170). NOTCH function is negatively regulated by EGFR-
activated C-JUN and inhibited by TP63, the latter being
overexpressed in numerous cases of HNSCC (171). Notch
signaling pathway is altered in 66% cases of HNSCC (172),
NOTCH1 gene presenting different percentages of mutations and
genetics variants, some of which being nonsense and missense
mutations (166,173).
Several clinical trials were designed to target Notch signaling in
patients with advanced solid tumors. An open-label phase 1a dose
escalation clinical trial study (NCT01778439) of brontictuzumab,a
monoclonal antibody, was designed to assess the safety,
immunogenicity, pharmacokinetics, biomarkers, and efficacy of
brontictuzumab in subjects with relapsed or refractory solid
tumors. The group around Ferrarotto, who contributed to this
clinical trial, reported significant clinical benefits in 6 of 36 patients,
with four subjects having prolonged (≥6months)disease
stabilization. In addition, brontictuzumab was well tolerated at the
maximum tolerated dose (174). More recently, two phase 1b studies
with parallel dose-escalations (NCT02784795; NCT02836600) were
designed to investigate the Notch inhibitor crenigacestat in patients
with advanced or metastatic cancer from a variety of solid tumors.
These clinical trials revealed that crenigacestat was poorly tolerated,
leading to lowered dosing and limited clinical activity in patients
with advanced or metastatic solid tumors (89,175,176).
2.8 Hypoxia and angiogenesis (HIF-
VEGF) pathway
The hypoxia and angiogenesis (HIF-VEGF) pathway is essential
for oxygen supply supplementation in solid tumors. The intense
metabolic activities of solid tumors require an increased oxygen
supply, which cannot be provided by the physiologically existing
capillary structure of tissues. Thus, small tumors a few millimeters
in diameter can be supplied by diffusion, but larger tumors with
increased oxygen requirements rapidly enter hypoxia (177). In
HNSCC, hypoxia is a common condition associated with poor
prognosis and 5-year survival approaching 0% (178). Recently,
Matic and collaborators searched potential biomarkers in HNSCC
by examining mRNA expression of five highly upregulated (CA9,
CASP14, LOX, GLUT3, SERPINE1) and four highly downregulated
(AREG, EREG, CCNB1, and KIF14) hypoxia-responsive genes in 32
HNSCC tumors and six adjacent normal oral tissue. The results
showed a significantly higher mRNA expression of the hypoxia
marker CA9 and SERPINE1 in all tumor biopsies compared to
normal tissue. Regarding the hypoxia-downregulated genes, the
authors observed higher KIF14 and AREG mRNA expression in
HNSCC patients than in the the control group. In conclusion, the
mRNA expression of KIF14 could be a potential diagnostic marker
and might serve as a predictor of treatment response in HNSCC
(Matic et al., 2024). Signaling via the hypoxia and angiogenesis
pathway begins with HIF1–2 proteins (hypoxia-inducible factors 1–
2), which heterodimerize, and the HIF1–HIF2 heterodimers are
translocated to the nucleus, where HIF1 promotes transcription of
some genes, including the angiogenesis inductors VEGFA-D
(Vascular Endothelial Growth Factors A-D) (67). Activation of
HIF1 and HIF2 and overexpression of VEGFA-D in HNSCC result
in carcinogenesis progression, increased aggressiveness, and poor
prognosis, with a 2-fold increase of 2-year mortality risk (161).
Bevacizumab, a monoclonal antibody, is an FDA-approved
VEGF inhibitor used in treating numerous cancers, either as a
single agent or combined with chemotherapy or radiotherapy (179).
In a phase III trial including 403 patients with HNSCC, adding
bevacizumab to platinum-based chemotherapy significantly
improvedtheresponserateandprogression-free survival.
However, it did not increase the median survival rate (91).
Several clinical trials have recently investigated the benefits of
bevacizumab in combination with immune and chemotherapy. A
Constantin et al. 10.3389/fonc.2024.1373821
Frontiers in Oncology frontiersin.org08
phase II multicenter study (NCT03818061) aims to assess the effects
of atezolizumab, a PD-L1 inhibitor, and bevacizumab in recurrent
or metastatic HNSCC, considering the ORR. Another phase II trial
(NCT00409565) compared bevacizumab with cetuximab, which has
an immune-mediated activity. The results published by Argiris and
collaborators revealed a significant reduction in tumor
vascularization, with an ORR of 16%, a disease control rate of
73%, and a generally well-tolerated response (90). Three phase II
trials are currently investigating the combination of bevacizumab,
cetuximab, and chemoradiation in HNSCC (NCT00968435;
NCT00703976; NCT01588431).
Tyrosine kinase inhibitors are small molecules acting by
inhibiting several targets within angiogenic signaling pathways,
including VEGFRs, EGFR, FGFR, and PDGFRs. In two phase II
clinical trials, sorafenib and sunitinib, a multi-kinase inhibitor, were
investigated in HNSCC patients and revealed minimal response
rates (180,181). A phase II trial of axitinib demonstrated a low
objective response rate but a favorable disease control rate of 77%
and median overall survival (OS) of 10.9 months with an acceptable
toxicity profile (182,183). Aurora kinase inhibitors are tested for
RB-deficient, HPV-positive HNSCCs (184).
2.9 Hippo signaling pathway
Identified nearly three decades ago during tissue growth
screening in Drosophila melanogaster, the Hippo signaling pathway
is evolutionarily conserved in mammals (185,186). Under
physiological conditions, the Hippo signaling pathway restricts
tissue growth in adult organisms by modulating cell proliferation,
differentiation, and migration in growing organs (185). Its
deregulation plays an important role in several diseases, including
cancer and various organ-specific diseases (187,188). In mammals,
the pathway involves over 30 proteins, such as MST1/2, SAV1,
MOB1A/B, and LATS1/2. These proteins phosphorylate YAP and
TAZ, tagging them for cytoplasmic degradation and preventing their
nuclear translocation, thus inhibiting transcription via TEADs and
SMADs. Activation occurs through FAT1, KIBRA, AJUBA, NF2,
RHO, AMPK, or by inactivation of STRIPAK complexes, which
regulate MST1/2 and MAP4Ks (189,190). In head and neck
squamous cell carcinoma, common aberrations include mutations
in FAT1, WWTR1/TAZ, YAP1, and MST2 (191,192). Since 2016,
several molecules targeting the Hippo pathway have been developed.
In nasopharyngeal carcinoma, MGH-CP1, an inhibitor of TEAD2/4
auto-palmitoylation, is in preclinical trials, reducing TEAD4-
mediated AKT signaling and inhibiting cell migration, invasion,
and resistance to cisplatin (50,189).
3 Epigenetic mechanisms
Acetylation is the transfer of an acetyl group from acetyl-CoA to
the amino epsilon group of lysine residues by a histone
acetyltransferase, neutralizing the positive charge of lysine
residues and exposing DNA to transcriptional complexes (193).
Other modifications consist of ubiquitination of lysine residues,
phosphorylation of serine residues, SUMOylation of lysine residues
(covalent interaction of a member of the SUMO, small ubiquitin-
like modifier, protein family through an enzymatic cascade
analogous but not similar to ubiquitination), and methylation of
lysine and arginine residues (194,195).
In HNSCC, global hypomethylation is more common in HPV-
negative tumors. It is associated with genetic instability, including
genome-wide loss-of-heterozygosity (LOH), single nucleotide
polymorphisms (SNP), and alternative oncogenic pathways (196).
Global hypomethylation was also linked with female gender and
worse survival, predominantly for older patients with a stage I or II
AJCC (American Joint Committee on Cancer) tongue squamous
cell carcinoma without lymph node involvement and with
postoperative radiotherapy (197). Assessment of the methylation
status of CALML5,DNAJC5G, and LY6D genes identified in ctDNA
from HNSCC patients demonstrated substantial predictive value in
early cancer diagnosis (198). FAM135B (Family with Sequence
Similarity 135 Member B) methylation appears to be associated
with good prognosis, while APBA1/MINT1 (Amyloid Beta
Precursor Protein Binding Family A Member 1), MINT31
(Methylated IN Tumors locus 31) DCC (Deleted In Colorectal
Carcinoma Netrin 1 Receptor) methylation with poor prognosis,
the latter one being also associated with bone invasiveness in the
mandible (199). Binding KRAS and having a role in apoptosis
induction, RASSF2 (Ras association domain-containing protein 1)
is intensely methylated. Other intensely methylated genes are
EDNRB (Endothelin Receptor Type B), methylated in 97% of
primary HNC tissues, and RARB (Retinoic Acid Receptor Beta),
involved in transcriptional control (199,200), and the tumor
suppressor genes PTEN,DAPK (death-associated protein kinase),
MGMT (O6-methylguanine-DNA methyltransferase), involved in
DNA repair, CDH1/ECAD (E-cadherin), involved in cell adhesion,
and RASSF1 (Ras association domain-containing protein 1),
involved in cell cycle control, apoptosis, and cell adhesion,
inactivation of which is present in several cancers (201).
Normally, cells of HNSCC are hypoacetylated (e.g., H3K9ac in
OSCC) (201) compared to normal mucosal cells, but histones in
these cells can be acetylated by factors secreted by endothelial cells,
in a paracrine manner. Consequently, acetylation induces the
amplification of BMI1, a transcriptional repressor associated with
poor survival and tumor aggressiveness, and vimentin, which marks
the epithelial-mesenchymal transition (202). Deacetylation is
mediated by histone deacetylases (HDACs), and HDACs
inhibition in vitro results in fewer cancer stem cells (CSCs) in
HNC. Thus, HDACs inhibition seems a promising strategy to
disrupt the population of CSCs in HNC to create a homogeneous
population of tumor cells characterized by well-defined biological
traits and predictable behaviors (203). Several HDAC inhibitors are
currently under evaluation in clinical trials for their efficiency in
HNC treatment. When combined with chemoradiation therapy,
vorinostat showed positive effects in HNC (NCT01064921).
Additionally, abexinostat is under evaluation with pembrolizumab
in an ongoing phase 1b dose-escalation trial for advanced solid
tumors, including metastatic HNSCC (NCT03590054).
Constantin et al. 10.3389/fonc.2024.1373821
Frontiers in Oncology frontiersin.org09
4 Non-coding RNAs
Non-coding RNAs do not encode proteins but have enzymatic,
structural, or regulatory functions and can control gene expression.
Depending on the number of nucleotides, they are short
(microRNA, miRNA) or long (lncRNA, long ncRNA). miRNA
are 21–23 nucleotides in size and bind partially complementary
regions of the 3’untranslated regions of several hundred mRNAs,
potentially interfering with gene expression and cell differentiation,
proliferation, and apoptosis. Although their aberrant expression can
trigger the malignant process, miRNAs can be used as tumor
suppressors due to their function in neoplastic development
(194). In HNC, the expression of numerous miRNAs is associated
with poor prognosis, decreased survival time, metastasis, and other
tumor processes. Thus, miR34 and miR17–92 overexpression and
miR137 underexpression are involved in apoptosis. miR210
overexpression and miR29 underexpression are associated with
genetic instability, miR21 overexpression, and miR210
underexpression are involved in evasion of the immune response,
miR26, and miR218 underexpression are associated with
inflammation. miR26, and miR125b underexpression are involved
in metabolism, overexpression of miR21 and miR155 and
underexpression of miR29 and miR139 promote proliferation.
Overexpression of miR26, miR125b, miR200b, miR96 and let-7d
and underexpression of miR139, miR218, miR29 and miR200 are
associated with metastasis. Overexpression of miR31, miR96,
miR205 and miR96 and underexpression of miR210, miR125b
and let-7d induce resistance to radiotherapy and chemotherapy
(204). Polymorphisms in miR-146, miR-149, miR-196, and miR-
499 may increase the risk of non-smokers infected with HPV,
overexpression of miR-21, miR-181b, miR-184, and miR-345 is
associated with malignant transformation, and overexpression of
miR-21, miR-34c, 184 and miR-155 promotes proliferation and
evasion of apoptosis (205), with miR-21 targeting the tumor
suppressor genes PTEN (Phosphatase and Tensin Homolog) and
PDCD4 (Programmed Cell Death 4) in some cancers (206).
Long ncRNAs are sequences of more than 200 nucleotides that
carry methyl-guanosine ends, are often spliced or polyadenylated,
and may be involved in chromatin remodeling. Being regulated by
associated transcription factors, they control the transcription or
can guide chromatin modification complexes to bind to specific
loci, silencing or activating gene expression (194). For example,
MIR31HG lncRNA appears to promote HIF1A and P21 expression,
inducing proliferation and tumorigenesis, and LINC00460 lncRNA
promotes the proliferation of HNSCC cells and epithelial-
mesenchymal transition-mediated metastasis. On the other hand,
SLC26A4-AS1 lncRNA interferes with cell invasiveness, migration,
and metastasis, with a tumor suppressor role (207)
Besides their utility as biomarkers, ncRNAs are also very good
therapeutic targets because they interact with numerous molecules
when altering different cellular processes within the tumor
microenvironment (208). The miRNA-based treatment relies on
the premise that diseases disrupt the miRNA profiles which can be
restored to normal (208).
Interestingly, the use of anti-miRNAs (miRNA sponges,
miRNA masks, or miRNA antagonists) to deplete oncogenic
miRNA as well as of miRNA mimetic molecules to simulate
endogenous tumor suppressor miRNAs, showed promising results
in limiting cancer cell growth in different HNC experimental
models (208–211). Several ncRNA therapeutics have reached
clinical trials in other malignancies. For instance, MRG-106
(cobomarsen), a miR-155 inhibitor, showed remarkable efficiency
and tolerability in a phase I clinical trial (NCT02580552) involving
15 patients with cutaneous T-cell lymphoma (212). Therefore,
although a nascent field of research, administering certain RNA-
based formulations alone or in conjunction with systemic therapies
seems to be a promising strategy for combating the burden of HNC.
5 Conclusions
The highly heterogeneous nature of HNC poses significant
challenges in patient management due to cellular origin and
anatomical site diversity, multiple etiological factors, and often
late-stage diagnosis, which limits therapeutic options and affects
survival and quality of life. Recent advancements in understanding
the pathogenesis and drug resistance mechanisms have led to the
development of various therapies.
Chemotherapy, chemoradiotherapy, targeted therapy, and
immunotherapy show varied efficacy based on HNC stage,
comorbidities, age, and previous treatments. New small molecule
inhibitors, developed as monotherapies or in combination with
other treatments, have shown promising results with moderate
adverse effects by targeting specific gene expressions. These
inhibitors have demonstrated fewer side effects compared to
traditional therapies like chemotherapy and radiotherapy,
enhancing patient tolerance. Notable drugs, such as the EGFR-
directed monoclonal antibody cetuximab, pembrolizumab, and
nivolumab, have achieved full FDA approval.
Despite these advancements, the complex interplay of multiple
cell-signaling pathways limits therapeutic responses. Continuous
clinical trials are necessary to confirm the effectiveness of these
therapies in diverse patient groups and stages of HNC, and to
identify suitable prognostic biomarkers for better therapeutic
strategies. Comprehensive genomic sequencing studies have
revealed numerous mutations in key signaling pathways,
highlighting the potential of ncRNAs as biomarkers in
HNC management.
Further improvements in treatment responses are needed, and
the clinical translation of new inhibitors remains crucial.
Combining these new agents with traditional treatments holds
significant potential. Advances in molecular approaches are
expected to enhance the success rate of targeted therapies,
offering better evaluations of their efficacy and opening new
research directions in personalized medicine for HNC diagnosis
and treatment.
Ongoing studies aim to refine the use of novel compounds in
therapeutic strategies, enabling precise identification of patients
Constantin et al. 10.3389/fonc.2024.1373821
Frontiers in Oncology frontiersin.org10
likely to benefit from these treatments, thus improving outcomes
and innovating HNC treatment approaches.
Author contributions
MC: Writing –original draft, Writing –review & editing. MCC:
Conceptualization, Funding acquisition, Writing –original draft,
Writing –review & editing. CB: Writing –review & editing. COV:
Writing –original draft, Writing –review & editing. REC: Writing –
original draft, Writing –review & editing. SB: Writing –review &
editing. RG: Writing –review & editing. GB: Writing –review
& editing.
Funding
The author(s) declare financial support was received for the
research, authorship, and/or publication of this article. We
acknowledge the financial support of C1.2.PFE-CDI.2021-587/
Contract no. 41PFE/30.12.2021; CNFIS-FDI-2024-F-0484; “The
core program within the National Research Development and
Innovation Plan, 2022–2027”, carried out with the support of the
Ministry of Research, Innovation and Digitalization (MCID),
project no. 23020101, Contract no. 7N from 3 January 2023;
Project No. RO1567-IBB05/2023 from the Institute of Biology of
the Romanian Academy; PN-III-P4-PCE-2021-0549 awarded by
Romanian Executive Agency for Higher Education, Research,
Development, and Innovation, and the support of the MRID,
project PNRR-I8 no 842027778, contract no 760096. The funders
had no role in the design of the study; in the collection, analyses, or
interpretation of data; in the writing of the manuscript; or in the
decision to publish the results.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
References
1. Iftikhar A, Islam M, Shepherd S, Jones S, Ellis I. What is behind the lifestyle risk
factors for head and neck cancer? Front Psychol. (2022) 13:960638. doi: 10.3389/
fpsyg.2022.960638
2. Farah CS. Molecular landscape of head and neck cancer and implications for
therapy. Ann Transl Med. (2021) 9:915. doi: 10.21037/atm-20–6264
3. Gormley M, Creaney G, Schache A, Ingarfield K, Conway DI. Reviewing the
epidemiology of head and neck cancer: definitions, trends and risk factors. Br Dent J.
(2022) 233:780–6. doi: 10.1038/s41415-022-5166-x
4. Miserocchi G, Spadazzi C, Calpona S, De Rosa F, Usai A, De Vita A, et al.
Precision medicine in head and neck cancers: genomic and preclinical approaches. J
Pers Med. (2022) 12:854. doi: 10.3390/jpm12060854
5. Moyses RA, Lopez RV, Cury PM, Siqueira SA, Curioni OA, Gois Filho JF, et al.
Significant differences in demographic, clinical, and pathological features in relation to
smoking and alcohol consumption among 1,633 head and neck cancer patients. Clinics
(Sao Paulo). (2013) 68:738–44. doi: 10.6061/clinics/2013(06)03
6. Chang CP, Siwakoti B, Sapkota A, Gautam DK, Lee YA, Monroe M, et al. Tobacco
smoking, chewing habits, alcohol drinking and the risk of head and neck cancer in
Nepal. Int J Cancer. (2020) 147:866–75. doi: 10.1002/ijc.32823
7. Hashibe M, Boffetta P, Zaridze D, Shangina O, Szeszenia-Dabrowska N, Mates D,
et al. Contribution of tobacco and alcohol to the high rates of squamous cell carcinoma
of the supraglottis and glottis in Central Europe. Am J Epidemiol. (2007) 165:814–20.
doi: 10.1093/aje/kwk066
8. CastellsagueX, Alemany L, Quer M, Halec G, Quiros B, Tous S, et al. HPV
involvement in head and neck cancers: comprehensive assessment of biomarkers in
3680 patients. J Natl Cancer Institute. (2016) 108:djv403. doi: 10.1093/jnci/djv403
9. Aboagye E, Agyemang-Yeboah F, Duduyemi BM, Obirikorang C. Human
papillomavirus detection in head and neck squamous cell carcinomas at a tertiary
hospital in sub-saharan africa. TheScientificWorldJournal. (2019) 2561530.
doi: 10.1155/2019/2561530
10. de SanjoseS, Serrano B, Tous S, Alejo M, Lloveras B, Quiros B, et al. Burden of
human papillomavirus (HPV)-related cancers attributable to HPVs 6/11/16/18/31/33/
45/52 and 58. JNCI Cancer Spectr. (2019) 2:pky045. doi: 10.1093/jncics/pky045
11. Bulane A, Goedhals D, Seedat RY, Goedhals J, Burt F. Human papillomavirus
DNA in head and neck squamous cell carcinomas in the Free State, South Africa. J Med
Virol. (2020) 92:227–33. doi: 10.1002/jmv.25556
12. Sabatini ME, Chiocca S. Human papillomavirus as a driver of head and neck
cancers. Br J Cancer. (2020) 122:306–14. doi: 10.1038/s41416–019-0602–7
13. MahmutovicL, Bilajac E, Hromic-JahjefendicA. Meet the insidious players:
review of viral infections in head and neck cancer etiology with an update on clinical
trials. Microorganisms. (2021) 9:1001. doi: 10.3390/microorganisms9051001
14. Vani NV, Madhanagopal R, Swaminathan R, Ganesan TS. Dynamics of oral
human papillomavirus infection in healthy population and head and neck cancer.
Cancer Med. (2023) 12:11731–45. doi: 10.1002/cam4.5686
15. Prabhu SR, Wilson DF. Evidence of Epstein-Barr virus association with head and
neck cancers: a review. J Can Dent Assoc. (2016) 82:g2.
16. Mulder FJ, Klufah F, Janssen FME, Farshadpour F, Willems SM, de Bree R, et al.
Presence of human papillomavirus and epstein-barr virus, but absence of merkel cell
polyomavirus, in head and neck cancer of non-smokers and non-drinkers. Front Oncol.
(2021) 10:560434. doi: 10.3389/fonc.2020.560434
17. Eells AC, Mackintosh C, Marks L, Marino MJ. Gastroesophageal reflux disease
and head and neck cancers: A systematic review and meta-analysis. Am J Otolaryngol.
(2020) 41:102653. doi: 10.1016/j.amjoto.2020.102653
18. Sharan RN, Mehrotra R, Choudhury Y, Asotra K. Association of betel nut with
carcinogenesis: revisit with a clinical perspective. PloS One. (2012) 7:e42759.
doi: 10.1371/journal.pone.0042759
19. Yu MZ, Wu MM, Chien HT, Liao CT, Su MJ, Huang SF, et al. Risk prediction
models for patients with head and neck cancer among the Taiwanese population.
Cancers (Basel). (2022) 14:5338. doi: 10.3390/cancers14215338
20. Chang CC, Lee WT, Hsiao JR, Ou CY, Huang CC, Tsai ST, et al. Oral hygiene
and the overall survival of head and neck cancer patients. Cancer Med. (2019) 8:1854–
64. doi: 10.1002/cam4.2059
21. Pandey D, Szczesniak M, Maclean J, Yim HCH, Zhang F, Graham P, et al.
Dysbiosis in head an d neck cancer: de termining optimal sampling site for oral
microbiome collection. Pathogens. (2022) 11:1550. doi: 10.3390/pathogens11121550
22. Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet.
(2008) 371:1695–709. doi: 10.1016/S0140-6736(08)60728-X
23. Mazul AL, Shivappa N, Hebert JR, Steck SE, Rodriguez-Ormaza N, Weissler M,
et al. Proinflammatory diet is associated with increased risk of squamous cell head and
neck cancer. Int J Cancer. (2018) 143:1604–10. doi: 10.1002/ijc.31555
Constantin et al. 10.3389/fonc.2024.1373821
Frontiers in Oncology frontiersin.org11
24. Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head
and neck squamous cell carcinoma. Nat Rev Dis Primers. (2020) 6:92. doi: 10.1038/
s41572–020-00224–3
25. Constantin M. Epidemiology, diagnosis, symptoms and TNM classification of
head and neck cancers. Rom Biotechnol Lett. (2022) 27:3699–712. doi: 10.25083/rbl/
27.5/3699.3712
26. Aung KL, Siu LL. Genomically personalized therapy in head and neck cancer.
Cancers Head Neck. (2016) 1:2. doi: 10.1186/s41199-016-0004-y
27. Ali J, Sabiha B, Jan HU, Haider SA, Khan AA, Ali SS. Genetic etiology of oral
cancer. Oral Oncol. (2017) 70:23–8. doi: 10.1016/j.oraloncology.2017.05.004
28. Huang Y, Zhao J, Sanghee MG, Lee G, Zhang J, Bi J, et al. Identification of novel
genetic variants predisposing to familial oral squamous cell carcinomas. Cell Discovery.
(2019) 5:57. doi: 10.1038/s41421–019-0126–6
29. Mali SB. Epigenetics: Promising journey so far but ways to go in head neck
cancer. Oral Oncol. (2022) 135:106194. doi: 10.1016/j.oraloncology.2022.106194
30. Leemans CR, Snijders PJF, Brakenhoff RH. The molecular landscape of head and
neck cancer. Nat Rev Cancer. (2018) 18:269–82. doi: 10.1038/nrc.2018.11
31. Economopoulou P, de Bree R, Kotsantis I, Psyrri A. Diagnostic tumor markers in
head and neck squamous cell carcinoma (HNSCC) in the clinical setting. Front Oncol.
(2019) 9:827. doi: 10.3389/fonc.2019.00827
32. Haider SP, Burtness B, Yarbrough WG, Payabvash S. Applications of radiomics
in precision diagnosis, prognostication and treatment planning of head and neck
squamous cell carcinomas. Cancers Head Neck. (2020) 5:6. doi: 10.1186/s41199–020-
00053–7
33. Kordbacheh F, Farah CS. Molecular pathways and druggable targets in head and
neck squamous cell carcinoma. Cancers (Basel). (2021) 13:3453. doi: 10.3390/
cancers13143453
34. Bernacchi V, DeGuzman PB. Cancer-related distress: symptom clusters in rural
head and neck cancer survivors. Clin J Oncol Nurs. (2023) 27:55–61. doi: 10.1188/
23.CJON.55–61
35. Van den Bossche V, Zaryouh H, Vara-Messler M, Vignau J, Machiels JP,
Wouters A, et al. Microenvironment-driven intratumoral heterogeneity in head and
neck cancers: clinical challenges and opportunities for precision medicine. Drug Resist
Updat. (2022) 60:100806. doi: 10.1016/j.drup.2022.100806
36. Poomsawat S, Sanguansin S, Punyasingh J, Vejchapipat P, Punyarit P.
Expression of cdk6 in head and neck squamous cell carcinoma. Clin Oral Investig.
(2016) 20:57–63. doi: 10.1007/s00784–015-1482–8
37. Angadi PV, Krishnapillai R. Cyclin D1 expression in oral squamous cell
carcinoma and verrucous carcinoma: correlation with histological differentiation.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. (2007) 103:e30–5. doi: 10.1016/
j.tripleo.2006.09.011
38. Goel B, Tiwari AK, Pandey RK, Singh AP, Kumar S, Sinha A, et al. Therapeutic
approaches for the treatment of head and neck squamous cell carcinoma-An update on
clinical trials. Transl Oncol. (2022) 21:101426. doi: 10.1016/j.tranon.2022.101426
39. Samra B, Tam E, Baseri B, Shapira I. Checkpoint inhibitors in head and neck
cancer: current knowledge and perspectives. JInvest.Med. (2018) 66:1023–30.
doi: 10.1136/jim-2018–000743
40. Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro GJr, et al.
Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for
recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-
048): a randomised, open-label, phase 3 study. Lancet. (2019) 394:1915–28.
doi: 10.1016/S0140–6736(19)32591–7
41. De Felice F, Cattaneo CG, Franco P. Radiotherapy and systemic therapies: focus
on head and neck cancer. Cancers (Basel). (2023) 15:4232. doi: 10.3390/
cancers15174232
42. Li Q, Tie Y, Alu A, Ma X, Shi H. Targeted therapy for head and neck cancer:
signaling pathways and clinical studies. Signal Transduct Target Ther. (2023) 8:31.
doi: 10.1038/s41392–022-01297–0
43. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational
landscape and significance across 12 major cancer types. Nature. (2013) 502:333–9.
doi: 10.1038/nature12634
44. Lyu H, Li M, Jiang Z, Liu Z, Wang X. Correlate the TP53 mutation and the
HRAS mutation with immune signatures in head and neck squamous cell cancer.
Comput Struct Biotechnol J. (2019) 17:1020–30. doi: 10.1016/j.csbj.2019.07.009
45. Klinakis A, Rampias T. TP53 mutational landscape of metastatic head and neck
cancer reveals patterns of mutation selection. EBioMedicine. (2020) 58:102905.
doi: 10.1016/j.ebiom.2020.102905
46. Basyuni S, Nugent G, Ferro A, Barker E, Reddin I, Jones O, et al. Value of p53
sequencing in the prognostication of head and neck cancer: a systematic review and
meta-analysis. Sci Rep. (2022) 12:20776. doi: 10.1038/s41598–022-25291–2
47. Nathan CA, Khandelwal AR, Wolf GT, Rodrigo JP, Mäkitie AA, Saba NF, et al.
TP53 mutations in head and neck cancer. Mol Carcinog. (2022) 61:385–91.
doi: 10.1002/mc.23385
48. Mandigo AC, Tomlins SA, Kelly WK, Knudsen KE. Relevance of pRB loss in
human Malignancies. Clin Cancer Res. (2022) 28:255–64. doi: 10.1158/1078–
0432.CCR-21–1565
49. Montalto FI, De Amicis F. Cyclin D1 in cancer: A molecular connection for cell
cycle control, adhesion and invasion in tumor and stroma. Cells. (2020) 9:2648.
doi: 10.3390/cells9122648
50. Wang J, Su W, Zhang T, Zhang S, Lei H, Ma F, et al. Aberrant Cyclin D1 splicing
in cancer: from molecular mechanism to therapeutic modulation. Cell Death Dis.
(2023) 14:244. doi: 10.1038/s41419–023-05763–7
51. Cancer Genome Atlas Network. Comprehensive genomic characterization of
head and neck squamous cell carcinomas. Nature. (2015) 517:576–82. doi: 10.1038/
nature14129
52. Golabek K, Raczka G, Gazdzicka J, Miskiewicz-Orczyk K, Zięba N, Krakowczyk
Ł, et al. Expression profiles of CDKN2A,MDM2,E2F2 and LTF genes in oral squamous
cell carcinoma. Biomedicines. (2022) 10:3011. doi: 10.3390/biomedicines10123011
53. Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, et al. Control of BRCA2
cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. (2006) 22:719–29.
doi: 10.1016/j.molcel.2006.05.022
54. Seiwert TY, Zuo Z, Keck MK, Khattri A, Pedamallu CS, Stricker T, et al.
Integrative and comparative genomic analysis of HPV-positive and HPV-negative head
and neck squamous cell carcinomas. Clin Cancer Res. (2015) 21:632–41. doi: 10.1158/
1078–0432.CCR-13–3310
55. Feldman R, Gatalica Z, Knezetic J, Reddy S, Nathan CA, Javadi N, et al.
Molecular profiling of head and neck squamous cell carcinoma. Head Neck. (2016)
38 Suppl 1:E1625–38. doi: 10.1002/hed.24290
56. Papalouka C, Adamaki M, Batsaki P, Zoumpourlis P, Tsintarakis A, Goulielmaki
M, et al. DNA damage response mechanisms in head and neck cancer: significant
implications for therapy and survival. Int J Mol Sci. (2023) 24:2760. doi: 10.3390/
ijms24032760
57. Wang YC, Lee KW, Tsai YS, Lu HH, Chen SY, Hsieh HY, et al. Downregulation
of ATM and BRCA1 predicts poor outcome in head and neck cancer: implications for
ATM-targeted therapy. J Pers Med. (2021) 11:389. doi: 10.3390/jpm11050389
58. Weber A, Langhanki L, Sommerer F, Markwarth A, Wittekind C, Tannapfel A.
Mutations of the BRAF gene in squamous cell carcinoma of the head and neck.
Oncogene. (2003) 22:4757–9. doi: 10.1038/sj.onc.1206705
59. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F,
et al. Roles of the Raf/MEK/ERK pathway in cell growth, Malignant transformation and
drug resistance. Biochim Biophys Acta. (2007) 1773:1263–84. doi: 10.1016/
j.bbamcr.2006.10.001
60. Roy M, Datta A. Cancer: genetics and important pathways. In: Cancer genetics
and therapeutics. Springer, Singapore (2019). doi: 10.1007/978-981-13-9471-3
61. KEGG. Pathways in cancer - Reference pathway (2020). Available online at:
https://www.genome.jp/kegg-bin/show_pathway?map05200 (Accessed 2023 Ian 09).
62. Rong C, Muller MF, Xiang F, Jensen A, Weichert W, Major G, et al. Adaptive
ERK signaling activation in response to therapy and in silico prognostic evaluation of
EGFR-MAPK in HNSCC. Br J Cancer. (2020) 123:288–97. doi: 10.1038/s41416–020-
0892–9
63. Dillon M, Lopez A, Lin E, Sales D, Perets R, Jain P. Progress on ras/MAPK
signaling research and targeting in blood and solid cancers. Cancers (Basel). (2021)
13:5059. doi: 10.3390/cancers13205059
64. Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, et al.
Oncogenic signaling pathways in the cancer genome atlas. Cell. (2018) 173:321–
337.e10. doi: 10.1016/j.cell.2018.03.035
65. Kazemein Jasemi NS, Ahmadian MR. Allosteric regulation of GRB2 modulates
RAS activation. Small GTPases. (2022) 13:282–6. doi: 10.1080/21541248.2022.2089001
66. Fernandez-Medarde A, De Las Rivas J, Santos E. 40 years of RAS-A historic
overview. Genes (Basel). (2021) 12:681. doi: 10.3390/genes12050681
67. AntraP, Hungyo H, Jain A, Ahmad S, Tandon V. Unraveling molecular
mechanisms of head and neck cancer. Crit Rev Oncol Hematol. (2022) 178:103778.
doi: 10.1016/j.critrevonc.2022.103778
68. Sasaki E, Masago K, Fujita S, Hanai N, Yatabe Y. Frequent KRAS and HRAS
mutations in squamous cell papillomas of the head and neck. J Pathol Clin Res. (2020)
6:154–9. doi: 10.1002/cjp2.157
69. Novoplansky O, Jagadeeshan S, Regev O, Menashe I, Elkabets M. Worldwide
prevalence and clinical characteristics of RAS mutations in head and neck cancer: A
systematic review and meta-analysis. Front Oncol. (2022) 12:838911. doi: 10.3389/
fonc.2022.838911
70. Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y, Hu LL. ERK/MAPK signaling pathway
and tumorigenesis. Exp Ther Med. (2020) 19:1997–2007. doi: 10.3892/etm.2020.8454
71. AlsahafiEN, Thavaraj S, Sarvestani N, Novoplansky O, Elkabets M, Ayaz B, et al.
EGFR overexpression increases radiotherapy response in HPV-positive head and neck
cancer through inhibition of DNA damage repair and HPV E6 downregulation. Cancer
Lett. (2021) 498:80–97. doi: 10.1016/j.canlet.2020.10.035
72. Ngan HL, Law CH, Choi YCY, Chan JY, Lui VWY. Precision drugging of the
MAPK pathway in head and neck cancer. NPJ Genom Med. (2022) 7:20. doi: 10.1038/
s41525–022-00293–1
73. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors
allosterically control GTP affinity and effector interactions. Nature. (2013) 503:548–51.
doi: 10.1038/nature12796
Constantin et al. 10.3389/fonc.2024.1373821
Frontiers in Oncology frontiersin.org12
74. Patricelli MP, Janes MR, Li LS, Hansen R, Peters U, Kessler LV, et al. Selective
inhibition of oncogenic KRAS output with small molecules targeting the inactive state.
Cancer Discovery. (2016) 6:316–29. doi: 10.1158/2159–8290.CD-15–1105
75. Janes MR, Zhang J, Li LS, Hansen R, Peters U, Guo X, et al. Targeting KRAS
mutant cancers with a covalent G12C-specific inhibitor. Cell. (2018) 172:578–589.e17.
doi: 10.1016/j.cell.2018.01.006
76. Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS
(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. (2019) 575:217–23.
doi: 10.1038/s41586–019-1694–1
77. Arbour KC, Khurana M, Dai T, Skoulidis F. Trial in progress: A phase 2 study of
sotorasib as first-line treatment in patients with stage IV non–small cell lung cancer
(NSCLC) whose tumors harbor a KRAS p.G12C mutation (CodeBreaK 201). JCO.
(2022) 40:TPS9150–TPS9150. doi: 10.1200/JCO.2022.40.16_suppl.TPS9150
78.GiraltJ,TrigoJ,NuytsS,OzsahinM,SkladowskiK,HatoumG,etal.
Panitumumab plus radiotherapy versus chemoradiotherapy in patients with
unresected, locally advanced squamous-cell carcinoma of the head and neck
(CONCERT-2): a randomised, controlled, open-label phase 2 trial. Lancet Oncol.
(2015) 16:221–32. doi: 10.1016/S1470–2045(14)71200–8
79. Ringash J, Waldron JN, Siu LL, Martino R, Winquist E, Wright JR, et al. Quality
of life and swallowing with standard chemoradiotherapy versus accelerated
radiotherapy and panitumumab in locoregionally advanced carcinoma of the head
and neck: A phase III randomised trial from the Canadian Cancer Trials Group (HN.
6). Eur J Cancer. (2017) 72:192–9. doi: 10.1016/j.ejca.2016.11.008
80. Irshad R, Haider G, Hashmi M, Hassan A. Efficacy of gefitinib and methorexate
in patients with advanced stage and recurrent head and neck cancer. Cureus. (2021) 13:
e15451. doi: 10.7759/cureus.15451
81. Baa AK, Sharma A, Bhaskar S, Biswas A, JeeBharti S, Thakar A, et al. A single-
arm feasibility phase II study of EMF (erlotinib + methotrexate + 5-fluorouracil)
regimen in platinum-refractory recurrent/metastatic head and neck squamous cell
carcinoma (R/M HNSCC). Ecancermedicalscience. (2022) 16:1451. doi: 10.3332/
ecancer.2022.1451
82. Kao HF, Liao BC, Huang YL, Huang HC, Chen CN, Chen TC, et al. Afatinib and
pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma
(ALPHA study): A phase II study with biomarker analysis. Clin Cancer Res. (2022)
28:1560–71. doi: 10.1158/1078–0432.CCR-21–3025
83. Evrard D, Dumont C, Gatineau M, Delord JP, Fayette J, Dreyer C, et al.
Targeting the Tumor Microenvironment through mTOR Inhibition and
Chemotherapy as Induction Therapy for Locally Advanced Head and Neck
Squamous Cell Carcinoma: The CAPRA Study. Cancers (Basel). (2022) 14:4509.
doi: 10.3390/cancers14184509
84. Juric D, Krop I, Ramanathan RK, Wilson TR, Ware JA, Sanabria Bohorquez SM,
et al. Phase I dose-escalation study of taselisib, an oral PI3K inhibitor, in patients with
advanced solid tumors. Cancer Discovery. (2017) 7:704–15. doi: 10.1158/2159–
8290.CD-16–1080
85. Kim HR, Kang HN, Yun MR, Ju KY, Choi JW, Jung DM, et al. Mouse-human co-
clinical trials demonstrate superior anti-tumour effects of buparlisib (BKM120) and
cetuximab combination in squamous cell carcinoma of head and neck. Br J Cancer.
(2020) 123:1720–9. doi: 10.1038/s41416–020-01074–2
86. Rodon J, Argiles G, Connolly RM, Vaishampayan U, de Jonge M, Garralda E,
et al. Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in
patients with advanced solid tumours. Br J Cancer. (2021) 125:28–37. doi: 10.1038/
s41416–021-01389–8
87. Qureshy Z, Li H, Zeng Y, Rivera J, Cheng N, Peterson CN, et al. STAT3
activation as a predictive biomarker for ruxolitinib response in head and neck cancer.
Clin Cancer Res. (2022) 28:4737–46. doi: 10.1158/1078–0432.CCR-22–0744
88. Munster P, Iannotti N, Cho DC, Kirkwood JM, Villaruz LC, Gibney GT, et al.
Combination of itacitinib or parsaclisib with pembrolizumab in patients with advanced
solid tumors: A phase I study. Cancer Res Commun. (2023) 3:2572–84. doi: 10.1158/
2767–9764.CRC-22–0461
89. Azaro A, Massard C, Tap WD, Cassier PA, Merchan J, Italiano A, et al. A phase
1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other
anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with
advanced or metastatic solid tumors. Invest New Drugs. (2021) 39:1089–98.
doi: 10.1007/s10637–021-01094–6
90. Argiris A, Kotsakis AP, Hoang T, Worden FP, Savvides P, Gibson MK, et al.
Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or
metastatic squamous cell carcinoma of the head and neck. Ann Oncol.(2013)
24:220–5. doi: 10.1093/annonc/mds245
91. Argiris A, Li S, Savvides P, Ohr JP, Gilbert J, Levine MA, et al. Phase III
randomized trial of chemotherapy with or without bevacizumab in patients with
recurrent or metastatic head and neck cancer. J Clin Oncol. (2019) 37:3266–74.
doi: 10.1200/JCO.19.00555
92. Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, et al. The
KRAS
G12C
inhibitor MRTX849 provides insight toward therapeutic susceptibility of
KRAS-mutant cancers in mouse models and patients. Cancer Discovery. (2020) 10:54–
71. doi: 10.1158/2159–8290.CD-19–1167
93. Fasano M, Della Corte CM, Viscardi G, Di Liello R, Paragliola F, Sparano F, et al.
Head and neck cancer: the role of anti-EGFR agents in the era of immunotherapy. Ther
Adv Med Oncol. (2021) 13:1758835920949418. doi: 10.1177/1758835920949418
94. Azoury SC, Gilmore RC, Shukla V. Molecularly targeted agents and
immunotherapy for the treatment of head and neck squamous cell cancer (HNSCC).
Discovery Med. (2016) 21:507–16.
95. Omura G, Honma Y, Matsumoto Y, Shinozaki T, Itoyama M, Eguchi K, et al.
Transnasal photoimmunotherapy with cetuximab sarotalocan sodium: Outcomes on
the local recurrence of nasopharyngeal squamous cell carcinoma. Auris Nasus Larynx.
(2023) 50:641–5. doi: 10.1016/j.anl.2022.06.004
96. Taberna M, Oliva M, Mesıa R. Cetuximab-containing combinations in locally
advanced and recurrent or metastatic head and neck squamous cell carcinoma. Front
Oncol. (2019) 9:383. doi: 10.3389/fonc.2019.00383
97. Chen TH, Pan YY, Lee TL, Wang LW, Tai SK, Chu PY, et al. Treatment
outcomes of cetuximab-containing regimen in locoregional recurrent and distant
metastatic head and neck squamous cell carcinoma. BMC Cancer. (2022) 22:1336.
doi: 10.1186/s12885–022-10440–7
98. Chu PL, Shihabuddeen WA, Low KP, Poon DJJ, Ramaswamy B, Liang ZG, et al.
Vandetanib sensitizes head and neck squamous cell carcinoma to photodynamic
therapy through modulation of EGFR-dependent DNA repair and the tumour
microenvironment. Photodiagnosis Photodyn Ther. (2019) 27:367–74. doi: 10.1016/
j.pdpdt.2019.06.008
99. Hintelmann K, Kriegs M, Rothkamm K, Rieckmann T. Improving the efficacy of
tumor radiosensitization through combined molecular targeting. Front Oncol. (2020)
10:1260. doi: 10.3389/fonc.2020.01260
100. Mesia R, Henke M, Fortin A, Minn H, Yunes Ancona AC, Cmelak A, et al.
Chemoradiotherapy with or without panitumumab in patients with unresected, locally
advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a
randomised, controlled, open-label phase 2 trial. Lancet Oncol. (2015) 16:208–20.
doi: 10.1016/S1470–2045(14)71198–2
101. Reddy BK, Lokesh V, Vidyasagar MS, Shenoy K, Babu KG, Shenoy A, et al.
Nimotuzumab provides survival benefit to patients with inoperable advanced
squamous cell carcinoma of the head and neck: a randomized, open-label, phase IIb,
5-yearstudyinIndianpatients.Oral Oncol. (2014) 50:498–505. doi: 10.1016/
j.oraloncology.2013.11.008
102. Menon N, Patil V, Noronha V, Joshi A, Bhattacharjee A, Satam BJ, et al. Quality
of life in patients with locally advanced head and neck cancer treated with concurrent
chemoradiation with cisplatin and nimotuzumab versus cisplatin alone - Additional
data from a phase 3 trial. Oral Oncol. (2021) 122:105517. doi: 10.1016/
j.oraloncology.2021.105517
103. Machiels JP, Subramanian S, Ruzsa A, Repassy G, Lifirenko I, Flygare A, et al.
Zalutumumab plus best supportive care versus best supportive care alone in patients
with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure
of platinum-based chemotherapy: an open-label, randomised phase 3 trial. Lancet
Oncol. (2011) 12:333–43. doi: 10.1016/S1470–2045(11)70034–1
104. Brondum L, Alsner J, Sørensen BS, Maare C, Johansen J, Primdahl H, et al.
Associations between skin rash, treatment outcome, and single nucleotide
polymorphisms in head and neck cancer patients receiving the EGFR-inhibitor
zalutumumab: results from the DAHANCA 19 trial. Acta Oncol. (2018) 57:1159–64.
doi: 10.1080/0284186X.2018.1464664
105. Tang X, He J, Li B, Zheng Y, Li K, Zou S, et al. Efficacy and safety of gefitinib in
patients with advanced head and neck squamous cell carcinoma: A meta-analysis of
randomized controlled trials. J Oncol. (2019) 2019:6273438. doi: 10.1155/2019/6273438
106. Jain AP, Radhakrishnan A, Pinto S, Patel K, Kumar M, Nanjappa V, et al. How
to achieve therapeutic response in erlotinib-resistant head and neck squamous cell
carcinoma? New insights from stable isotope labeling with amino acids in cell culture-
based quantitative tyrosine phosphoproteomics. OMICS. (2021) 25:605–16.
doi: 10.1089/omi.2021.0057
107. Harrington K, Berrier A, Robinson M, Remenar E, Housset M, de Mendoza FH,
et al. Randomised Phase II study of oral lapatinib combined with chemoradiotherapy in
patients with advanced squamous cell carcinoma of the head and neck: rationale for
future randomised trials in human papilloma virus-negative disease. Eur J Cancer.
(2013) 49:1609–18. doi: 10.1016/j.ejca.2012.11.023
108. Rascio F, Spadaccino F, Rocchetti MT, Castellano G, Stallone G, Netti GS, et al.
The pathogenic role of PI3K/AKT pathway in cancer onset and drug resistance: an
updated review. Cancers (Basel). (2021) 13:3949. doi: 10.3390/cancers13163949
109. Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X. Targeting PI3K in cancer:
mechanisms and advances in clinical trials. Mol Cancer. (2019) 18:26. doi: 10.1186/
s12943-019-0954-x
110. He Y, Sun MM, Zhang GG, Yang J, Chen KS, Xu WW, et al. Targeting PI3K/
Akt signal transduction for cancer therapy. Signal Transduct Target Ther. (2021) 6:425.
doi: 10.1038/s41392–021-00828–5
111. Khezri MR, Ghasemnejad-Berenji M, Moloodsouri D. Hesperetin and the
PI3K/AKT pathway: Could their interaction play a role in the entry and replication
of the SARS-CoV-2? J Food Biochem. (2022) 46:e14212. doi: 10.1111/jfbc.14212
112. Naderali E, Valipour B, Khaki AA, Soleymani Rad J, Alihemmati A, Rahmati
M, et al. Positive effects of PI3K/akt signaling inhibition on PTEN and P53 in
prevention of acute lymphoblastic leukemia tumor cells. Adv Pharm Bull. (2019)
9:470–80. doi: 10.15171/apb.2019.056
113. Nam HJ, Chae S, Jang SH, Cho H, Lee JH. The PI3K-Akt mediates oncogenic
Met-induced centrosome amplification and chromosome instability. Carcinogenesis.
(2010) 31:1531–40. doi: 10.1093/carcin/bgq133
Constantin et al. 10.3389/fonc.2024.1373821
Frontiers in Oncology frontiersin.org13
114. Hervieu A, Kermorgant S. The role of PI3K in met driven cancer: A recap. Front
Mol Biosci. (2018) 5:86. doi: 10.3389/fmolb.2018.00086
115. Gougis P, Moreau Bachelard C, Kamal M, Gan HK, Borcoman E, Torossian N,
et al. Clinical development of molecular targeted therapy in head and neck squamous
cell carcinoma. JNCI Cancer Spectr. (2019) 3:pkz055. doi: 10.1093/jncics/pkz055
116. Raj S, Kesari KK, Kumar A, Rathi B, Sharma A, Gupta PK, et al. Molecular
mechanism(s) of regulation(s) of c-MET/HGF signaling in head and neck cancer. Mol
Cancer. (2022) 21:31. doi: 10.1186/s12943–022-01503–1
117. Fujino T, Suda K, Koga T, Hamada A, Ohara S, Chiba M, et al. Foretinib can
overcome common on-target resistance mutations after capmatinib/tepotinib
treatment in NSCLCs with MET exon 14 skipping mutation. J Hematol Oncol.
(2022) 15:79. doi: 10.1186/s13045-022-01299-z
118. Khedkar HN, Chen LC, Kuo YC, Wu ATH, Huang HS. Multi-omics
identification of genetic alterations in head and neck squamous cell carcinoma and
therapeutic efficacy of HNC018 as a novel multi-target agent for c-MET/STAT3/AKT
signaling axis. Int J Mol Sci. (2023) 24:10247. doi: 10.3390/ijms241210247
119. Hudeckova M, KouckyV, Rottenberg J, Gal B. Gene mutations in circulating
tumour DNA as a diagnostic and prognostic marker in head and neck cancer-A
systematic review. Biomedicines. (2021) 9:1548. doi: 10.3390/biomedicines9111548
120. Tsai PJ, Lai YH, Manne RK, Tsai YS, Sarbassov D, Lin HK, et al. Akt: a key
transducer in cancer. J BioMed Sci. (2022) 29:76. doi: 10.1186/s12929–022-00860–9
121. Islam M, Jones S, Ellis I. Role of akt/protein kinase B in cancer metastasis.
Biomedicines. (2023) 11:3001. doi: 10.3390/biomedicines11113001
122. Enomoto A, Murakami H, Asai N, Morone N, Watanabe T, Kawai K, et al. Akt/
PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell. (2005)
9:389–402. doi: 10.1016/j.devcel.2005.08.001
123. Chan CH, Lee SW, Li CF, Wang J, Yang WL, Wu CY, et al. Deciphering the
transcriptional complex critical for RhoA gene expression and cancer metastasis. Nat
Cell Biol. (2010) 12:457–67. doi: 10.1038/ncb2047
124. Wise-Draper TM, Bahig H, Tonneau M, Karivedu V, Burtness B. Current
therapy for metastatic head and neck cancer: evidence, opportunities, and challenges.
Am Soc Clin Oncol Educ Book. (2022) 42:1–14. doi: 10.1200/EDBK_350442
125. Liu WL, Gao M, Tzen KY, Tsai CL, Hsu FM, Cheng AL, et al. Targeting
Phosphatidylinositide3-Kinase/Akt pathway by BKM120 for radiosensitization in
hepatocellular carcinoma. Oncotarget. (2014) 5:3662–72. doi: 10.18632/oncotarget.1978
126. Jhaveri K, Chang MT, Juric D, Saura C, Gambardella V, Melnyk A, et al. Phase I
basket study of taselisib, an isoform-selective PI3K inhibitor, in patients with PIK3CA-
mutant cancers. Clin Cancer Res. (2021) 27:447–59. doi: 10.1158/1078–0432.CCR-20–
2657
127. Juric D, Rodon J, Tabernero J, Janku F, Burris HA, Schellens JHM, et al.
Phosphatidylinositol 3-kinase a-selective inhibition with alpelisib (BYL719) in
PIK3CA-altered solid tumors: results from the first-in-human study. J Clin Oncol.
(2018) 36:1291–9. doi: 10.1200/JCO.2017.72.7107
128. Batalini F, Xiong N, Tayob N, Polak M, Eismann J, Cantley LC, et al. Phase 1b
clinical trial with alpelisib plus olaparib for patients with advanced triple-negative
breast cancer. Clin Cancer Res. (2022) 28:1493–9. doi: 10.1158/1078–0432.CCR-21–
3045
129. Ghosh S, Shah PA, Johnson FM. Novel systemic treatment modalities including
immunotherapy and molecular targeted therapy for recurrent and metastatic head and
neck squamous cell carcinoma. Int J Mol Sci. (2022) 23:7889. doi: 10.3390/
ijms23147889
130. Fayette J, Digue L C, Segura-Ferlay C, Treilleux I, Wang Q, Lefebvre G, et al.
Buparlisib (BKM120) in refractory head and neck squamous cell carcinoma harbouring
or not a PI3KCA mutation: A phase II multicenter trial. Ann Oncol. (2019) 30:v455.
doi: 10.1093/annonc/mdz252.012
131. Soulieres D, Licitra L, Mesıa R, RemenarE
, Li SH, Karpenko A, et al. Molecular
alterations and buparlisib efficacy in patients with squamous cell carcinoma of the head
and neck: biomarker analysis from BERIL-1. Clin Cancer Res. (2018) 24:2505–16.
doi: 10.1158/1078–0432.CCR-17–2644
132. Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, et al. Wnt/b-catenin signalling:
function, biological mechanisms, and therapeutic opportunities. Signal Transduct
Target Ther. (2022) 7:3. doi: 10.1038/s41392–021-00762–6
133. Pascual-Carreras E, Marın-Barba M, Castillo-Lara S, Coronel-Cordoba P,
Magri MS, Wheeler GN, et al. Wnt/b-catenin signalling is required for pole-specific
chromatin remodeling during planarian regeneration. Nat Commun. (2023) 14:298.
doi: 10.1038/s41467-023-35937-y
134. Werner J, Boonekamp KE, Zhan T, Boutros M. The roles of secreted wnt
ligands in cancer. Int J Mol Sci. (2023) 24:5349. doi: 10.3390/ijms24065349
135. Chowdhury P, Nagamalini BR, Singh J, Ashwini BK, Sharada, Swaminathan U.
Expression of b-catenin in oral leukoplakia and oral submucous fibrosis: An
immunohistochemical study. JOralMaxillofacPathol. (2021) 25:124–30.
doi: 10.4103/jomfp.JOMFP_41_20
136. Xie J, Huang L, Lu YG, Zheng DL. Roles of the wnt signaling pathway in head
and neck squamous cell carcinoma. Front Mol Biosci. (2021) 7:590912. doi: 10.3389/
fmolb.2020.590912
137. Prgomet Z, Andersson T, Lindberg P. Higher expression of WNT5A protein in
oral squamous cell carcinoma compared with dysplasia and oral mucosa with a normal
appearance. Eur J Oral Sci. (2017) 125:237–46. doi: 10.1111/eos.12352
138. Zhang W, Yan Y, Gu M, Wang X, Zhu H, Zhang S, et al. High expression levels
of Wnt5a and Ror2 in laryngeal squamous cell carcinoma are associated with poor
prognosis. Oncol Lett. (2017) 14:2232–8. doi: 10.3892/ol.2017.6386
139. Qin L, Yin YT, Zheng FJ, Peng LX, Yang CF, Bao YN, et al. WNT5A promotes
stemness characteristics in nasopharyngeal carcinoma cells leading to metastasis and
tumorigenesis. Oncotarget. (2015) 6:10239–52. doi: 10.18632/oncotarget.3518
140. Sakamoto T, Kawano S, Matsubara R, Goto Y, Jinno T, Maruse Y, et al. Critical
roles of Wnt5a-Ror2 signaling in aggressiveness of tongue squamous cell carcinoma and
production of matrix metalloproteinase-2 via DNp63b-mediated epithelial-mesenchymal
transition. Oral Oncol. (2017) 69:15–25. doi: 10.1016/j.oraloncology.2017.03.019
141. Xie H, Ma Y, Li J, Chen H, Xie Y, Chen M, et al. WNT7A promotes EGF-induced
migration of oral squamous cell carcinoma cells by activating b-catenin/MMP9-mediated
signaling. Front Pharmacol. (2020) 11:98. doi: 10.3389/fphar.2020.00098
142. Shiah SG, Hsiao JR, Chang WM, Chen YW, Jin YT, Wong TY, et al.
Downregulated miR329 and miR410 promote the proliferation and invasion of oral
squamous cell carcinoma by targeting Wnt-7b. Cancer Res. (2014) 74 :7560–72.
doi: 10.1158/0008–5472.CAN-14–0978
143. Purwaningsih NMS, Khor GH, Nik Mohd Rosdy NMM, Abdul Rahman EO.
Wnt pathway in oral cancer: A review update. Saudi Dent J. (20 21) 33:813–8.
doi: 10.1016/j.sdentj.2021.08.002
144. Aditya J, Smiline Girija AS, Paramasivam A, Vijayashree Priyadharsini J.
Genetic alterations in Wnt family of genes and their putative association with head
and neck squamous cell carcinoma. Genomics Inform. (2021) 19:e5. doi: 10.5808/
gi.20065
145. Gao X, Hannoush RN. Single-cell imaging of Wnt palmitoylation by the
acyltransferase porcupine. Nat Chem Biol. (2014) 10:61–8. doi: 10.1038/nchembio.1392
146. Galli LM, Anderson MO, Gabriel Fraley J, Sanchez L, Bueno R, Hernandez DN,
et al. Determination of the membrane topology of PORCN, an O-acyl transferase that
modifies Wnt signalling proteins. Open Biol. (2021) 11:200400. doi: 10.1098/
rsob.200400
147. Flanagan DJ, Woodcock SA, Phillips C, Eagle C, Sansom OJ. Targeting ligand-
dependent wnt pathway dysregulation in gastrointestinal cancers through porcupine
inhibition. Pharmacol Ther. (2022) 238:108179. doi: 10.1016/j.pharmthera.2022.108179
148. Le PN, McDermott JD, Jimeno A. Targeting the Wnt pathway in human
cancers: therapeutic targeting with a focus on OMP-54F28. Pharmacol Ther. (2015)
146:1–11. doi: 10.1016/j.pharmthera.2014.08.005
149. Diamond JR, Becerra C, Richards D, Mita A, Osborne C, O’Shaughnessy J, et al.
Phase Ib clinical trial of the anti-frizzled antibody vantictumab (OMP-18R5) plus
paclitaxel in patients with locally advanced or metastatic HER2-negative breast cancer.
Breast Cancer Res Treat. (2020) 184:53–62. doi: 10.1007/s10549-020-05817-w
150. Pecina-Slaus N, AnicicS, Bukovac A, Kafka A. Wnt signaling inhibitors and
their promising role in tumor treatment. Int J Mol Sci. (2023) 24:6733. doi: 10.3390/
ijms24076733
151. Lai SY, Johnson FM. Defining the role of the JAK–STAT pathway in head and
neck and thoracic Malignancies: implications for future therapeutic approaches. Drug
Resist Updat. (2010) 13:67–78. doi: 10.1016/j.drup.2010.04.001
152. Sen M, Pollock NI, Black J, DeGrave KA, Wheeler S, Freilino ML, et al. JAK
kinase inhibition abrogates STAT3 activation and head and neck squamous cell
carcinoma tumor growth. Neoplasia. (2015) 17:256–64. doi: 10.1016/j.neo.2015.01.003
153. Cedars E, Johnson DE, Grandis JR. Jak/STAT signaling in head and neck
cancer. Curr Cancer Res. (2018), 155–84. doi: 10.1007/978–3-319–78762-6_6
154. Gutie
rrez-Hoya A, Soto-Cruz I. Role of the JAK/STAT pathway in cervical
cancer: its relationship with HPV E6/E7 oncoproteins. Cells (2020) 9:2297.
doi: 10.3390/cells9102297
155. Majoros A, Platanitis E, Kernbauer-Hölzl E, Rosebrock F, Müller M, Decker T.
Canonical and non-canonical aspects of JAK–STAT signaling: lessons from interferons
for cytokine responses. Front Immunol. (2017) 8:29. doi: 10.3389/fimmu.2017.00029
156. Anderson K, Ryan N, Nedungadi D, Lamenza F, Swingler M, Siddiqui A,
et al. STAT1 is regulated by TRIM24 and promotes immunosuppression in head and
neck squamous carcinoma cells, but enhances T cell antitumour immunity in the
tumour microenvironment. Br J Cancer. (2022) 127:624–36. doi: 10.1038/s41416-
022-01853-z
157. Nakagawa T, Oda G, Kawachi H, Ishikawa T, Okamoto K, Uetake H. Nuclear
expression of p-STAT3 is associated with poor prognosis in ER(-) breast cancer. Clin
Pract. (2022) 12:157–67. doi: 10.3390/clinpract12020020
158. Manuelli V, Pecorari C, Filomeni G, Zito E. Regulation of redox signaling in
HIF-1-dependent tumor angiogenesis. FEBS J. (2022) 289:5413–25. doi: 10.1111/
febs.16110
159. Park H, Lee S, Lee J, Moon H, Ro SW. Exploring the JAK/STAT signaling
pathway in hepatocellular carcinoma: unraveling signaling complexity and therapeutic
implications. Int J Mol Sci. (2023) 24:13764. doi: 10.3390/ijms241813764
160. Rah B, Rather RA, Bhat GR, Baba AB, Mushtaq I, Farooq M, et al. JAK/STAT
signaling: molecular targets, therapeutic opportunities, and limitations of targeted
inhibitions in solid Malignancies. Front Pharmacol. (2022) 13:821344. doi: 10.3389/
fphar.2022.821344
161. Hu Q, Bian Q, Rong D, Wang L, Song J, Huang HS, et al. JAK/STAT pathway:
Extracellular signals, diseases, immunity, and therapeutic regimens. Front Bioeng
Biotechnol. (2023) 11:1110765. doi: 10.3389/fbioe.2023.1110765
Constantin et al. 10.3389/fonc.2024.1373821
Frontiers in Oncology frontiersin.org14
162. Kowshik J, Baba AB, Giri H, Deepak Reddy G, Dixit M, Nagini S. Astaxanthin
inhibits JAK/STAT-3 signaling to abrogate cell proliferation, invasion and angiogenesis
in a hamster model of oral cancer. PloS One. (2014) 9:e109114. doi: 10.1371/
journal.pone.0109114
163. Stover DG, Gil DelAlcazar CR, Brock J, GuoH, Overmoyer B, Balko J,et al. Phase
II study of ruxolitinib, a selective JAK1/2 inhibitor, in patients with metastatic triple-
negative breast cancer. NPJ Breast Cancer. (2018) 4:10. doi: 10.1038/s41523-018-0060-z
164. von Bubnoff N, Ihorst G, Grishina O, Röthling N, Bertz H, Duyster J, et al.
Ruxolitinib in GvHD (RIG) study: a multicenter, randomized phase 2 trial to determine
the response rate of Ruxolitinib and best available treatment (BAT) versus BAT in
steroid-refractory acute graft-versus-hos t disease (aGvHD) (NCT02396628). BMC
Cancer. (2018) 18:1132. doi: 10.1186/s12885–018-5045–7
165. Andersson ER, Sandberg R, Lendahl U. Notch signaling: simplicity in design,
versatility in function. Development. (2011) 138:3593–612. doi: 10.1242/dev.063610
166. Sun W, Gaykalova DA, Ochs MF, Mambo E, Arnaoutakis D, Liu Y, et al.
Activation of the NOTCH pathway in head and neck cancer. Cancer Res. (2014)
74:1091–104. doi: 10.1158/0008–5472.CAN-13–1259
167. Weaver AN, Burch MB, Cooper TS, Della Manna DL, Wei S, Ojesina AI, et al.
Notch signaling activation is associated with patient mortality and increased FGF1-
mediated invasion in squamous cell carcinoma of the oral cavity. Mol Cancer Res.
(2016) 14:883–91. doi: 10.1158/1541–7786.MCR-16–0114
168. Talora C, Sgroi DC, Crum CP, Dotto GP. Specific down-modulation of Notch1
signaling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late
steps of Malignant tran sformation. Genes Dev. (2002) 16:2252–63. doi: 10.1101/gad.988902
169. Luo Z, Mu L, Zheng Y, Shen W, Li J, Xu L, et al. NUMB enhances Notch
signaling by repressing ubiquitination of NOTCH1 intracellular domain. J Mol Cell
Biol. (2020) 12:345–58. doi: 10.1093/jmcb/mjz088
170. Henningsen KM, Manzini V, Magerhans A, Gerber S, Dobbelstein M. MDM2-
driven ubiquitination rapidly removes p53 from its cognate promoters. Biomolecules.
(2021) 12:22. doi: 10.3390/biom12010022
171. Porcheri C, Meisel CT, Mitsiadis T. Multifactorial contribution of notch
signaling in head and neck squamous cell carcinoma. Int J Mol Sci. (2019) 20:1520.
doi: 10.3390/ijms20061520
172. Pickering CR, Zhang J, Yoo SY, Bengtsson L, Moorthy S, Neskey DM, et al.
Integrative genomic characterization of oral squamous cell carcinoma identifies frequent
somatic drivers. Cancer Discovery. (2013) 3:770–81. doi: 10.1158/2159–8290.CD-12–0537
173. Shah PA, Huang C, LiQ, Kazi SA, Byers LA, Wang J,et al. NOTCH1 signaling in
head and neck squamous cell carcinoma. Cells. (2020) 9:2677. doi: 10.3390/cells9122677
174. Ferrarotto R, Mishra V, Herz E, Yaacov A, Solomon O, Rauch R, et al. AL101, a
gamma-secre tase inhibitor, has potent antitumor activity agai nst adenoid cystic
carcinoma with activated NOTCH signaling. Cell Death Dis. (2022) 13:678.
doi: 10.1038/s41419–022-05133–9
175. Doi T, Tajimi M, Mori J, Asou H, Inoue K, Benhadji KA, et al. A phase 1 study
of crenigacestat (LY3039478), the Notch inhibitor, in Japanese patients with advanced
solid tumors. Invest New Drugs. (2021) 39:469–76. doi: 10.1007/s10637–020-01001–5
176. Massard C, Cassier PA, Azaro A, Anderson B, Yuen E, Yu D, et al. A phase 1b
study of crenigacestat (LY3039478) in combination with gemcitabine and cisplatin or
gemcitabine and carboplatin in patients with advanced or metastatic solid tumors.
Cancer Chemother Pharmacol. (2022) 90:335–44. doi: 10.1007/s00280-022-04461-z
177. Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes,
consequences, challenges and opportunities. Cell Mol Life Sci. (2020) 77:1745–70.
doi: 10.1007/s00018–019-03351–7
178. Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, et al.
Prognostic value of tumor oxygenation in 397 head and neck tumors after primary
radiation therapy. An international multi-center study. Radiother Oncol. (2005) 77:18–
24. doi: 10.1016/j.radonc.2005.06.038
179. De Aguiar RB, de Moraes JZ. Exploring the immunological mechanisms
underlying the anti-vascular endoth elial growth factor activity in tumors. Front
Immunol. (2019) 10:1023. doi: 10.3389/fimmu.2019.01023
180. Fountzilas G, Fragkoulidi A, Kalogera-Fountzila A, Nikolaidou M, Bobos M,
Calderaro J, et al. A phase II study of sunitinib in patients with recurrent and/or
metastatic non-nasopharyngeal head and neck cancer. Cancer Chemother Pharmacol.
(2010) 65:649–60. doi: 10.1007/s00280–009-1070–1
181. Williamson SK, Moon J, Huang CH, Guaglianone PP, LeBlanc M, Wolf GT,
et al. Phase II evaluation of sorafenib in advanced and metastatic squamous cell
carcinoma of the head and neck: Southwest Oncology Group Study S0420. J Clin Oncol.
(2010) 28:3330–5. doi: 10.1200/JCO.2009.25.6834
182. Swiecicki PL, Zhao L, Belile E, Sacco AG, Chepeha DB, Dobrosotskaya I, et al. A
phase II study evaluating axitinib in patients with unresectable, recurrent or metastatic head
and neck cancer. Invest New Drugs. (2015) 33:1248–56. doi: 10.1007/s10637–015-0293–8
183. Swiecicki PL, Bellile EL, Brummel CV, Brenner JC, Worden FP. Efficacy of
axitinib in metastatic head and neck cancer with novel radiographic response criteria.
Cancer. (2021) 127:219–28. doi: 10.1002/cncr.33226
184. Ghosh S, Mazumdar T, Xu W, Powell RT, Stephan C, Shen L, et al. Combined
TRIP13 and aurora kinase inhibition induces apoptosis in human papillomavirus-driven
cancers. Clin Cancer Res. (2022) 28:4 479–93. doi: 10.1158/1078–0432.CCR-22–1627
185. Meng Z, Moroishi T, Guan KL. Mechanisms of Hippo pathway regulation.
Genes Dev. (2016) 30:1–17. doi: 10.1101/gad.274027.115
186. Chen Y, Han H, Seo G, Vargas RE, Yang B, Chuc K, etal. Systematic analysis of
the Hippo pathway organization and oncogenic alteration in evolution. Sci Rep. (2020)
10:3173. doi: 10.1038/s41598–020-60120–4
187. Zheng Y, Pan D. The hippo signaling pathway in development and disease. Dev
Cell. (2019) 50:264–82. doi: 10.1016/j.devcel.2019.06.003
188. Fu M, Hu Y, Lan T, Guan KL, Luo T, Luo M. The Hippo signalling pathway and
its implications in human health and diseases. Signal Transduct Target Ther. (2022)
7:376. doi: 10.1038/s41392–022-01191–9
189. Lv L, Zhou X. Targeting Hippo signaling in cancer: novel perspectives and
therapeutic potential. MedComm. (2020) 2023) 4:e375. doi: 10.1002/mco2.375
190. Peng Z, Gong Y, Liang X. Role of FAT1 in health and disease. Oncol Lett. (2021)
21:398. doi: 10.3892/ol.2021.12659
191. Santos-de-Frutos K, Segrelles C, Lorz C. Hippo pathway and YAP signaling
alterations in squamous cancer of the head and neck. J Clin Med. (2019) 8:2131.
doi: 10.3390/jcm8122131
192. Faraji F, Ramirez SI, Anguiano Quiroz PY, Mendez-Molina AN, Gutkind JS.
Genomic hippo pathway alterations and persistent YAP/TAZ activation: new
hallmarks in head and neck cancer. Cells. (2022) 11:1370. doi: 10.3390/cells11081370
193. Liu R, Wu J, Guo H, Yao W, Li S, Lu Y, et al. Post-translational modifications of
histones: Mechanisms, biological functions, and therapeutic targets. MedComm. (2023)
2020):e292. doi: 10.1002/mco2.292
194. Osorio JC, Castillo A. Epigenetic mechanisms in head and neck cancer. In:
Bulgin D, edit or. New aspects in molecular and cellular mechanisms of human
carcinogenesis. InTech, Rijeka (2016). p. 67–95.
195. Bais MV. Impact of epigenetic regulation on head and neck squamous cell
carcinoma. J Dent Res. (2019) 98:268–76. doi: 10.1177/0022034518816947
196. Camuzi D, Buexm LA, Lourenco SQC, Esposti DD, Cuenin C, Lopes MSA, et al.
HPV infection leaves a DNA methylation signature in oropharyngeal cancer affecting
both coding genes and transposable elements. Cancers (Basel). (2021) 13:3621.
doi: 10.3390/cancers13143621
197. Chen HC, Yang CM, Cheng JT, Tsai KW, Fu TY, Liou HH, et al. Global DNA
hypomethylation is associated with the development and poor prognosis of tongue
squamous cell carcinoma. J Oral Pathol Med. (2016) 45:409–17. doi: 10.1111/jop.12381
198. Misawa K, MochizukiD, Imai A, Mima M, Misawa Y, Mineta H. Analysis of site-
specific methylation of tumor-related genes in head and neck cancer: potential utility as
biomarkers for prognosis. Cancers (Basel). (2018) 10:27. doi: 10.3390/cancers10010027
199. Liouta G, Adamaki M, Tsintarakis A, Zoumpourlis P, Liouta A, Agelaki S, et al.
DNA methylation as a diagnostic, prognostic, and predictive biomarker in head and
neck cancer. Int J Mol Sci. (2023) 24:2996. doi: 10.3390/ijms24032996
200. Zhou C, Ye M, Ni S, Li Q, Ye D, Li J, et al. DNA methylation biomarkers for
head and neck squamous cell carcinoma. Epigenetics. (2018) 13:398–409. doi: 10.1080/
15592294.2018.1465790
201. Gazdzicka J, Gołabek K, Strzelczyk JK, Ostrowska Z. Epigenetic modifications in
head and neck cancer. Biochem Genet.(2020)58:213–44. doi: 10.1007/s10528–019-09941–1
202. Le JM, Squarize CH, Castilho RM. Histone modifications: Targeting head and
neck cancer stem cells. World J Stem Cells. (2014) 6:511–25. doi: 10.4252/wjsc.v6.i5.511
203. Giudice FS, Pinto DSJr, Nör JE, Squarize CH, Castilho RM. Inhibition of histone
deacetylase impacts cancer stem cells and induces epithelial-mesenchyme transition of
head and neck cancer. PloS One. (2013) 8:e58672. doi: 10.1371/journal.pone.0058672
204. Romanowska K, Sobecka A, Rawłuszko-Wieczorek AA, Suchorska WM,
Golusinski W. Head and neck squamous cell carcinoma: epigenetic landscape.
Diagnostics (Basel). (2020) 11:34. doi: 10.3390/diagnostics11010034
205. Gupta S, Kumar P, Maini J, Kaur H, Das BC. Epigenetic biomarkers in head and
neck cancer. Epigenetic biomarkers in head and neck cancer. J Cancer Genet And
Biomarkers. (2018) 1:41–50. doi: 10.14302/issn.2572–3030.jcgb-18–2428
206. Cao LQ, Yang XW, Chen YB, Zhang DW, Jiang XF, Xue P, et al. Exosomal
miR-21 regulates the TETs/PTENp1/PTEN pathway to promote hepatocellular
carcinoma growth. Mol Cancer. (2019) 18:148. doi: 10.1186/s12943–019-1075–2
207. Gougousis S, Petanidis S, Poutoglidis A, Tsetsos N, Vrochidis P, Skoumpas I,
et al. Epigenetic editing and tumor-dependent immunosuppressive signaling in head
and neck Malignancies. Oncol Lett. (2022) 23:196. doi: 10.3892/ol.2022.13317
208. Bhattacharjee R, Prabhakar N, Kumar L, Bhattacharjee A, Kar S, Malik S, et al.
Crosstalk between long noncoding RNA and microRNA in Cancer. Cell Oncol (Dordr).
(2023) 46:885–908. doi: 10.1007/s13402–023-00806–9
209. Barrera LN, Ridley PM, Bermejo-Rodriguez C, Costello E., Perez-Mancera P.A.
The role of microRNAs in the modulation of cancer-associated fibroblasts activity
during pancreatic cancer pathogenesis. JPhysiolBiochem. (2023) 79:193–204.
doi: 10.1007/s13105–022-00899–0
210. Chakrabortty A, Patton DJ, Smith BF, Agarwal P. miRNAs: potential as biomarkers
and therapeutic targets for cancer. Genes (Basel). (2023) 14:1375. doi: 10.3390/genes14071375
211. Sadeghi MS, LotfiM, Soltani N, Farmani E, Fernandez JHO, Akhlaghitehrani S,
et al. Recent advances on high-efficiency of microRNAs in different types of lung cancer: a
comprehensive review. Cancer Ce ll Int. (2023) 23:284. doi: 10.1186/s12935-023-03133-z
212. Foss FM, Querfeld C, Porcu P, Kim YH, Pacheco T, Halwani AS, et al. Phase 1 trial
evaluating MRG-106, a synthetic inhibitor of microRNA-155, in patients with cutaneous t-cell
lymphoma (CTCL). JClinOncol. (2017) 35:7564. doi: 10.1200/JCO.2017.35.15_suppl.7564
Constantin et al. 10.3389/fonc.2024.1373821
Frontiers in Oncology frontiersin.org15
