MET-Targeting Anticancer Drugs—De Novo Design and Identification by Drug Repurposing

Abstract

The Met protein is a cell surface receptor tyrosine kinase predominantly expressed in epithelial cells. Aberrant regulation of MET is manifested by numerous mechanisms including amplification, mutations, deletion, fusion of the MET proto-oncogene, and protein overexpression. They represent the common causes of drug resistance to conventional and targeted chemotherapy in numerous cancer types. There is also accumulating evidence that MET/HGF signaling drives an immunosuppressive tumor microenvironment and dampens the efficacy of cancer immunotherapy. Substantial research effort has been invested in designing Met-targeting drugs with different mechanisms of action. In this review, we summarized the current preclinical and clinical research about the development of Met-targeting drugs for cancer therapeutics. Early attempts to evaluate Met-targeted therapies in clinical trials without selecting the appropriate patient population did not produce satisfactory outcomes. In the era of personalized medicine, cancer patients harboring MET exon 14 alterations or MET amplification have been found to respond well to Met-inhibitor therapy. The application of Met inhibitors to overcome drug resistance in cancer patients is discussed in this paper. Given that kinases play critical roles in cancer development, numerous kinase-mediated signaling pathways are attractive targets for cancer therapy. Existing kinase inhibitors have also been repurposed to new kinase targets or new indications in cancer. On the other hand, non-oncology drugs have also been repurposed for treating cancer through kinase inhibition as one of their reported anticancer mechanisms.

Full text

Citation: To, K.K.-W.; Leung, K.-S.;
Cho, W.C.-S. MET-Targeting
Anticancer Drugs—De Novo Design
and Identification by Drug
Repurposing. Drugs Drug Candidates
2023,2, 591–623. https://doi.org/
10.3390/ddc2030031
Academic Editor: Jean
Jacques Vanden Eynde
Received: 16 May 2023
Revised: 11 July 2023
Accepted: 13 July 2023
Published: 18 July 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Review
MET-Targeting Anticancer Drugs—De Novo Design and
Identification by Drug Repurposing
Kenneth Kin-Wah To 1 ,* , Kwong-Sak Leung 2,3 and William Chi-Shing Cho 4
1School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
2Department of Computer Science and Engineering, The Chinese University of Hong Kong,
Hong Kong, China; ksleung@cse.cuhk.edu.hk
3Department of Applied Data Science, Hong Kong Shue Yan University, Hong Kong, China
4Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China; chocs@ha.org.hk
*Correspondence: kennethto@cuhk.edu.hk; Tel.: +(852)-3943-8017; Fax: +(852)-2603-5295
Abstract:
The Met protein is a cell surface receptor tyrosine kinase predominantly expressed in
epithelial cells. Aberrant regulation of MET is manifested by numerous mechanisms including
amplification, mutations, deletion, fusion of the MET proto-oncogene, and protein overexpression.
They represent the common causes of drug resistance to conventional and targeted chemotherapy
in numerous cancer types. There is also accumulating evidence that MET/HGF signaling drives
an immunosuppressive tumor microenvironment and dampens the efficacy of cancer immunother-
apy. Substantial research effort has been invested in designing Met-targeting drugs with different
mechanisms of action. In this review, we summarized the current preclinical and clinical research
about the development of Met-targeting drugs for cancer therapeutics. Early attempts to evaluate
Met-targeted therapies in clinical trials without selecting the appropriate patient population did
not produce satisfactory outcomes. In the era of personalized medicine, cancer patients harboring
MET exon 14 alterations or MET amplification have been found to respond well to Met-inhibitor
therapy. The application of Met inhibitors to overcome drug resistance in cancer patients is discussed
in this paper. Given that kinases play critical roles in cancer development, numerous kinase-mediated
signaling pathways are attractive targets for cancer therapy. Existing kinase inhibitors have also been
repurposed to new kinase targets or new indications in cancer. On the other hand, non-oncology
drugs have also been repurposed for treating cancer through kinase inhibition as one of their reported
anticancer mechanisms.
Keywords:
MET amplification; MET exon 14 alterations; drug repurposing; kinase inhibitors; resis-
tance
1. Introduction
The MET proto-oncogene is located on chromosome 7q21-31 and encodes a receptor
tyrosine kinase Met (also known as c-Met) for the hepatocyte growth factor (HGF) [
1
–
3
].
HGF is a cytokine produced by stromal cells and fibroblasts to stimulate the migration of
epithelial cells. The binding of HGF to Met triggers the dimerization of the receptor and
autophosphorylation of the Met kinase domain, which subsequently activates downstream
signaling pathways to promote cell survival and proliferation [
4
,
5
]. The HGF/Met axis
also plays a critical role in regulating embryonic development in normal physiology [
6
]. In
addition, it also controls the epithelial-to-mesenchymal (EMT) transition process and pro-
motes the differentiation of multipotent cells to numerous other cell types [
7
]. Furthermore,
the HGF/Met pathway is also involved in tissue regeneration [8].
The oncogenic role of Met was first reported in a human osteosarcoma cell line carrying
aTPR (translocated promoter region)-MET genomic rearrangement after exposure to the
carcinogen N-methyl-N
0
-nitro-N-nitrosoguanidine [
9
]. Hyperactivation of the HGF/Met
signaling pathway is frequently observed in numerous cancer cell types and it is generally
Drugs Drug Candidates 2023,2, 591–623. https://doi.org/10.3390/ddc2030031 https://www.mdpi.com/journal/ddc

Drugs Drug Candidates 2023,2592
associated with dismal patient survival [
10
]. Aberrant activation of MET is usually caused
by mutations, genomic rearrangement, amplification, and protein overexpression, which
promotes cancer development by activating the downstream PI3K/AKT, Ras/MAPK,
JAK/STAT, SRC, and Wnt/β-catenin signaling pathways [11–14].
With the high propensity of MET dysregulation in numerous cancers, Met is consid-
ered an attractive therapeutic target for cancer therapy [
15
,
16
]. However, early attempts to
target Met for cancer therapy in the clinical setting were not satisfactory. To date, only a few
Met inhibitors have been clinically approved. The major hurdle is the weak Met-inhibitory
activity of the drug candidates and a lack of an appropriate patient selection for the clinical
trials [17–19].
MET-exon-14-skipping mutations represent a valuable predictive biomarker to identify
non-small-cell lung cancer (NSCLC) patients who are likely to respond well to Met tyrosine
kinase inhibitors (TKIs) [
20
]. MET exon 14 contains the amino acid residue Y1003, which
is critical for the binding of the Met protein to an E3 ubiquitin ligase CBL. MET-exon-
14-skipping mutations produce a shorter exon-14-spliced Met protein, thereby impairing
CBL-mediated Met protein degradation and subsequently leading to the constitutional
activation of MET signaling. Moreover, Met TKIs were also shown to display promising
efficacy in NSCLC patients harboring other MET abnormalities including amplification or
gene fusions. Following this successful clinical observation, numerous newer Met TKIs are
currently under clinical investigation.
This review aims to provide an updated summary of the design and preclinical and
clinical research of Met-targeting drugs for cancer treatment. Unlike early clinical trials in-
vestigating Met-targeted therapy in unselected patient cohorts, more recent clinical studies
focusing on MET exon 14 alterations and MET amplification have produced encouraging
treatment responses to Met-inhibitor therapy. The novel strategies of using Met inhibitors to
overcome drug resistance and potentiate immunotherapy in cancer patients are discussed.
Drug repurposing refers to the application of clinically approved drugs with characterized
pharmacological properties and known adverse effect profiles to new indications. Given
that kinases play critical roles in cancer development, numerous kinase-mediated signaling
pathways are attractive targets for cancer therapy, and existing kinase inhibitors have also
been repurposed to new kinase targets or new indications in cancer. On the other hand,
non-oncology drugs have been repurposed for treating cancer through kinase inhibition as
one of their reported anticancer mechanisms.
2. Recent Development of Met-Targeting Drug Candidates for Cancer Therapy
Currently, there are four major strategies to inhibit the MET signaling pathway for
cancer therapy: (i) preventing the extracellular binding of Met and HGF by a neutralizing
antibody; (ii) blocking the dimerization of Met; (iii) preventing the phosphorylation of the
tyrosine kinase domain of Met with a small molecule inhibitor; and (iv) blocking other
signaling molecules downstream of MET. Their site of action in the HGF/MET pathway is
illustrated in Figure 1. The updated status about development of the first three strategies
(i–iii) is summarized below. Strategy (iv) involves the inhibition of very diverse signaling
pathways and is out of the scope of the current review. Readers may refer to other recent
excellent reviews on the topic for more detailed descriptions [21].
2.1. Antibody-Based Inhibitors of the HGF-MET Axis
Given that the interaction of HGF and Met is a prerequisite for the activation of the
MET signaling pathway, both proteins are promising molecular targets for therapeutic
intervention. Therapeutic agents designed to target HGF or Met have been evaluated alone
as a monotherapy or in combination with other targeted cancer therapies. They are in
various stages of preclinical and clinical development. HGF-neutralizing antibodies work
by binding to the fully processed HGF molecules and preventing them from interacting
with the Met receptor. On the other hand, anti-Met monoclonal antibodies (mAb) work
by competing with HGF, and they do not trigger Met receptor dimerization for signal

Drugs Drug Candidates 2023,2593
transduction. Decoys of Met have been designed to interact with intact Met or HGF, or both,
to disrupt the dimerization of the Met receptor. To date, no antibody-based biotherapeutics
targeting Met/HGF have been clinically approved. The latest research and development
of these antibody-based therapeutic agents (including classical therapeutic monoclonal
antibodies, bispecific antibodies, and antibody–drug conjugates (ADC)) is summarized in
the following section.
Figure 1.
Schematic diagram showing the various molecular mechanisms causing MET dysregulation
in cancer cells and their potential therapeutic interventions. (1) Met protein overexpression due to
MET gene amplification or MET-exon-14-skipping mutations. (2) Ligand-dependent Met activation
due to excessive HGF secretion from stromal cells. (3) Mutations of the Met kinase domain which
induce ligand-independent MET activation through autophosphorylation. (4) MET-exon-14-skipping
mutations dramatically reduce binding of the E3 ubiquitin ligase CBL to the receptor and suppress
Met protein degradation. (5) MET amplification induces ligand-independent MET signaling via
receptor autodimerization and autophosphorylation. The major therapeutic strategies targeting MET
dysregulation are depicted next to the respective mechanism: (a) Met-targeting proteolysis-targeting
chimera (PROTAC) to promote degradation of the oncogenic Met protein; (b) anti-HGF and anti-Met
monoclonal antibodies (mAb), which inhibit ligand–receptor interaction and/or prevent receptor
dimerization; (c) Met-binding DNA aptamers to compete with HGF for Met binding and prevent
Met dimerization; (d) Met TKIs to inhibit the receptor kinase activity; and (e) specific inhibitors of
downstream signaling molecules (e.g., STAT3 inhibitors, mTOR inhibitors, Met inhibitors).
2.1.1. Anti-HGF mAbs
HGF, also known as scatter factor (SF), is a paracrine multifunctional cytokine secreted
by mesenchymal cells that regulates cell growth, motility, and morphogenesis. It is secreted
as an inactive polypeptide, which is cleaved by serine proteases into an alpha chain
(69 kDa) and a beta chain (34 kDa) during activation. A disulfide bond formation between
the alpha and beta chains generates the active heterodimeric molecule. Upon the binding

Drugs Drug Candidates 2023,2594
of HGF to its receptor, Met, the downstream intracellular signal transduction pathways are
activated to regulate cell proliferation, migration, invasion, angiogenesis, and apoptosis.
Elevated tumoral and plasma levels of HGF have been reported in patients with breast
cancer, glioma, multiple myeloma, and sarcomas [
22
,
23
]. HGF-targeting antibodies bind to
extracellular HGF to prevent its interaction with Met and the subsequent activation of the
HGF/Met pathway.
Rilotumumab (AMG-102) is an mAb that was developed against the full-length HGF
protein. It is the first HGF inhibitor to reach phase 3 clinical testing. It binds to the HGF
β
-chain and inhibits HGF–Met interaction. In a phase 1 trial (NCT01791374), rilotumumab
was well-tolerated in patients with solid tumors, with only low-grade adverse events being
observed (fatigue, constipation, anorexia, nausea, and vomiting) [
24
]. In a phase 2 trial
(NCT00719550) studying the combination of rilotumumab with epirubicin, cisplatin, and
capecitabine, overall survival (OS) and progression-free survival (PFS) were extended in
Met-positive patients with gastric cancer or gastroesophageal junction adenocarcinoma [
25
].
However, two phase 3 clinical trials (RILOMET-1 and RILOMET-2) were halted because
of a lack of efficacy or patient deaths [
26
]. In the RILOMET-1 trial, a statistically higher
number of patient deaths were observed in the rilotumumab arm (128 deaths) than in the
placebo arm (107 deaths). Moreover, a shorter median OS was also noted in the patient
group receiving rilotumumab than the placebo (9.6 months versus 11.5 months, hazard
ratio: 1.37, p= 0.016). However, further subgroup analysis also did not reveal any survival
benefit achieved by rilotumumab in patients with a higher Met expression [26].
Ficlatuzumab (AV-299) is another humanized HGF-targeting mAb under clinical inves-
tigation. Results from a phase 2 study in lung cancer patients harboring EGFR mutations
demonstrated that the VeriStrat-poor patient subgroup may gain survival benefits from the
inclusion of ficlatuzumab in the treatment [
27
]. The VeriStrat test is a serum-based assay
that identifies responders according to a serum mass spectrometry proteomic signature.
The intensity and pattern of eight mass spectral features were captured by matrix-assisted
laser desorption/ionization time-of-flight mass spectrometry and compared with a con-
trol. The test examined pretreatment serum samples from the patients and assign them
to a “VeriStrat Good” or “VeriStrat Poor” status as an indicator of treatment response.
However, in the phase 2 FOCAL trial (NCT02318368) evaluating a first-line treatment
with a ficlatuzumab–erlotinib combination versus erlotinib monotherapy in VeriStrat-poor
patients with EGFR-mutated NSCLC, the study was prematurely terminated due to a high
discontinuation rate in the drug combination group [28].
MP0250 is a designed-ankyrin-repeat-protein (DARPin)-based drug candidate that
interacts with both HGF and vascular endothelial growth factor (VEGF) [
29
]. It also has an
additional domain to bind to human serum albumin (HSA), which enhances its plasma
half-life and promotes tumor penetration. DARPins are antibody-mimetic-engineered
proteins. Compared to antibodies, DARPins are smaller in size, and they generally exhibit
favorable pharmacokinetic profiles and facilitate both a high-affinity binding and efficacy.
MP0250 comprises one anti-VEGF-A, one anti-HGF, and two anti-human serum albumin
(HSA) DARPin
®
domains within a single polypeptide chain. The HSA-binding DARPin
domain serves as a carrier to extend the half-life and leads to a more favorable pharmacoki-
netic profile. In preclinical studies, MP0250 was shown to bind to and inhibit both HGF
and VEGF [
29
]. When used alone or in combination with bortezomib, MP0250 inhibited
myeloma cell migration, invasion, and bone destruction in an orthotopic mouse model of
multiple myeloma [
30
]. Currently, MP0250 is under clinical investigation in a multicen-
ter phase 2 trial (NCT03136653) in combination with bortezomib and dexamethasone for
patients with refractory and relapsed multiple myeloma.
2.1.2. Anti-Met mAbs
Onartuzumab (MetMAb) is an mAb raised against Met, which interferes with the
binding of the HGF
α
-chain to its Met-ligand-binding domain [
31
]. Results from a phase
2 trial (NCT00854308) showed a superior clinical efficacy from the onartuzumab–erlotinib

Drugs Drug Candidates 2023,2595
combination compared with erlotinib alone in lung cancer patients with a tumor expressing
a high Met protein level [
32
,
33
]. However, subsequent testing in another phase 3 OAM4971g
trial (NCT01456325, METLung) was discontinued due to shorter patient survival in the
onartuzumab–erlotinib combination group [19,34].
Emibetuzumab (LY2875358) is a humanized bivalent IgG4 monoclonal antibody tar-
geting the Met protein. It blocks HGF binding to Met and therefore the downstream
HGF-induced signaling pathways [
35
]. Unlike onartuzumab, emibetuzumab also induces
the internalization and degradation of the Met receptor protein, thus enabling it to exert
an anticancer effect in both HGF-dependent and -independent (including MET-amplified)
cancer [
35
]. In a recent phase 2 trial (NCT0190652) comparing an emibetuzumab–erlotinib
combination with emibetuzumab monotherapy in stage IV NSCLC patients with acquired
resistance to erlotinib, the disease control rate (DCR) and PFS were higher for the drug
combination (50%/3.3 months) than for emibetuzumab alone (26%/1.6 months) [
36
]. Simi-
lar results were observed in patients with a high tumoral Met protein expression (i.e., >60%
of cells expressing Met at >2 + IHC staining intensity).
ARGX-111 was developed by screening from a panel of anti-Met mAbs generated by
the SIMPLE antibody platform [
37
]. It is a fully human mAb. Its Fc region was afucosylated
(where the oligosaccharides in the Fc region of the antibody do not have any fucose sugar
unit) for increased tissue penetration and enhanced antibody-dependent cell-mediated
cytotoxicity (ADCC) [
37
]. In cancer-cell-line studies, ARGX-111 was shown to inhibit both
HGF-dependent and -independent MET activation [
37
]. It exhibited potent cytotoxicity
through ADCC against human cancer cell lines and patient-derived leukemia cells express-
ing variable Met levels. In orthotopic tumor models, ARGX-111 was found to remarkably
reduce the number of circulating tumor cells and suppress distant metastasis [
37
]. In a
phase 1 clinical trial (NCT02055066) for patients with hematological and solid tumors,
ARGX-111 displayed favorable safety profiles [
38
]. One patient (1/16) with metastatic,
MET-amplified gastric cancer refractory to platinum- and taxane-based chemotherapy
maintained a stable disease for 6 months following treatment with ARGX-111.
SAIT301 is a Met-specific mAb that promotes leucine-rich repeats (LRR) and
immunoglobulin-like domain-containing protein 1 (LRIG1)-mediated Met degradation in a
Cbl-independent manner [
39
]. This humanized anti-Met antibody was originally derived
from the mouse antibody F46. It binds to the Sema domain of Met with a higher affinity
than HGF, subsequently promoting the cellular internalization and degradation of the
receptor in both an HGF-dependent and -independent manner [
40
]. Moreover, SAIT301
also competes with HGF for binding to Met, thus preventing the downstream signaling
pathways and leading to reduced cell proliferation and diminished cancer invasiveness
in an HGF-dependent manner [
40
]. Findings from a phase 1 trial (NCT02296879) in Met-
overexpressed colorectal cancer patients showed that SAIT301 was well-tolerated [
41
].
Partial response and stable disease were achieved by SAIT301 in the cohort of 16 metastatic
colorectal cancer patients [41].
Telisotuzumab (ABT-700 or h224G11) is a humanized bivalent Met-specific mAb that
inhibits Met dimerization and activation [
42
]. It gave rise to long-term tumor regression
in tumor xenograft models harboring Met overexpression, amplification, and autocrine
HGF stimulation [
42
]. When combined with other chemotherapeutic drugs (including
gemcitabine and docetaxel), telisotuzumab produced a synergistic anticancer effect and
a more prolonged duration of a tumor-suppressive effect [
42
]. Recent data from a phase
1 dose-escalation and -expansion trial (NCT01472016) showed that telisotuzumab was
well-tolerated in patients bearing MET-amplified solid tumors [
43
]. Due to the promising
anti-Met and anti-tumor activities of telisotuzumab, an antibody–drug conjugate (ADC)
called telisotuzumab vedotin (ABBV-399) is being developed, which will be described in a
later section on ADC [44].
Recently, an interesting strategy of employing two anti-Met mAbs to target non-
overlapping Met epitopes called Sym015 has been reported [
45
]. Sym015 binds to human
and monkey Met with a high affinity and promotes rapid Met cellular internalization and

Drugs Drug Candidates 2023,2596
degradation, which is accompanied by dampened MET signaling in both HGF-dependent
and -independent manners. In various cancer cell lines with or without MET overexpres-
sion or amplification, Sym015 was shown to inhibit proliferation, migration, invasion, and
prominent cell death [
45
,
46
]. Moreover, Sym015 was also found to induce complement-
dependent cytotoxicity (CDC) and ADCC to promote cellular lysis [
45
,
46
]. Importantly,
xenograft tumors generated by cancer cells that are resistant to emibetuzumab were re-
ported to be sensitive to Sym015 [
46
], thus suggesting its utility in treating tumors that have
acquired resistance after previous anti-Met antibody-based therapy. Currently, Sym015 is
being investigated in a phase 1 trial for patients with advanced solid tumors (NCT02648724).
Employing an antibody-decoy strategy, a hybrid molecule capable of simultaneously
inhibiting HGF and Met has been developed [
47
]. The hybrid molecule was constructed
by the “head-to-tail” or “tail-to-head” fusion of a single-chain Fab derived from a Met
mAb (MvDN30) with a “decoy” (i.e., recombinant engineered Met extracellular domain;
decoyMET). The anti-Met mAb facilitated the removal of Met from the cell surface, whereas
the decoy provided the HGF-sequestering ability (Figure 2). To prevent antibody/decoy
interaction and subsequent neutralization, a specific amino acid residue in the extracellular
domain of Met (lysine 842) critical for MvDN30 binding was engineered to K842E in
the recombinant decoyMET [
47
]. Using an orthotopic pancreatic tumor model in SCID
mice, the MvDN30–decoyMET hybrid molecule was shown to sequester Met and HGF
simultaneously, thereby inhibiting HGF-induced Met downstream signaling to inhibit
cancer growth and metastatic spread [47].
Figure 2.
Schematic diagram showing the design of a MvDN30–decoyMET hybrid molecule to
simultaneously inhibit HGF and Met. HGF: hepatocyte growth factor; Fab: fragment antigen-binding
region; Fc: fragment crystallizable region.
2.1.3. Bispecific Antibodies Simultaneously Targeting Met and Other Signaling Proteins
Simultaneously Targeting Met and EGFR
The crosstalk between Met and other oncogenic signaling pathways to propel cancer
development has been well established [
48
]. The aberrant regulation of MET also con-
tributes to drug resistance acquired by cancer cells following EGFR-targeted therapy [
49
].
Therefore, the simultaneous inhibition of both MET and EGFR signaling cascades repre-
sents a promising approach to enhance the anticancer effects of Met- and EGFR-targeting
therapies. To date, five bispecific antibodies targeting both Met and EGFR (MET-HER1,
amivantamab, LY3164530, ME22S, and B10v5x225-H/M) have been reported. The proof-of-
concept evaluation of this approach was first established in the investigation of Met-HER1
in 2013 [
50
]. Currently, amivantamab has advanced to phase 2 clinical trials, whereas
LY3164530 was discontinued due to toxicities and limited clinical efficacy [51].

Drugs Drug Candidates 2023,2597
Simultaneously Targeting Met and VEGFR-2
VEGFR-2 is an important molecular target for anti-angiogenesis therapy in cancer
treatment [
52
]. Bevacizumab is a humanized anti-VEGF monoclonal antibody clinically
approved for cancer therapy by inhibiting the VEGF signaling pathway. However, it is well
known that increased Met expression representsa major resistance mechanism contributing
to bevacizumab treatment [
53
]. To this end, the development of bispecific monoclonal
antibody targeting both Met and VEGFR2 to overcome bevacizumab has been reported [
54
].
The amino acid sequences from onartuzumab (an anti-Met mAb) and tanibirumab (an anti-
VEGFR2 mAb) were used to construct one such bispecific Met- and VEGFR2-targeting mAb
(called “bsVEMET”) using an engineered heterodimeric fragment crystallizable region (Fc)
platform [
54
]. In human vascular endothelial cells, HUVEC, overexpressing both Met and
VEGFR2, bsVEMET was confirmed to bind to the two target antigens simultaneously with
high affinities [
54
]. Moreover, bsVEMET was also found to inhibit the HGF/VEGF-induced
phosphorylation of Met and VEGF2 and their downstream signaling molecules. Further-
more, in a gastric cancer MKN45 tumor xenograft model
in vivo
, the antitumor effect of
bsVEMET was stronger than that derived from the individual use of either onartuzumab
or tanibirumab and was also slightly more effective than that mediated by the combination
of the two mAbs [54].
Simultaneously Targeting Met and PD-1
Bispecific mAbs simultaneously inhibiting MET signaling and blocking PD-1 (anti-
programmed cell death receptor) for the restoration of T-cell-mediated anticancer response
have also been developed. PD-1 is an inhibitory checkpoint protein expressed on im-
mune cells (such as T cells, B cells, and natural killer cells), which normally suppress a
host’s immunity from attacking other cells in the body. Upon the binding of PD-1 to its
major ligand, PD-L1, expressing on tumor cells, the T-cell-mediated cancer-killing effect
is suppressed. In recent years, various mAbs targeting either PD-1 or PD-L1 (such as
nivolumab, pembrolizumab, and ipilimumab) have been approved for cancer immunother-
apy. Numerous strategies have also been developed to potentiate the clinical outcome
of immunotherapeutic drugs. To this end, bispecific mAbs (including Met-PD1 BsAb,
DVD-Ig, and IgG-ScFv) targeting both Met and PD-1 have been designed and evaluated
in preclinical studies
[55–57]
. In gastric and NSCLC cell lines, these bispecific mAbs were
shown to interact with Met and inhibit HGF-dependent cancer proliferation and migration
and induce apoptosis. Using a co-culture system consisting of cancer cells and peripheral
blood T cells, Met-PD-1 was shown to partially restore the ability of T cells to produce
interleukin 2 and other cytokines, but the effect was only very modest [
55
]. In a gastric
MKN45 tumor xenograft model, the three bispecific mAbs were found to moderately de-
lay tumor growth [
55
–
57
]. Moreover, a concurrent administration of the bispecific mAb
and peripheral blood leucocytes (PBMC) was only found to slightly enhance the overall
tumor-growth-suppressive effect. Therefore, targeting PD-1 by using bispecific mAbs
for restoring cytotoxic T cell activity may not produce a dramatic antitumor effect in an
experimental setting.
2.1.4. Antibody–Drug Conjugates (ADC) Targeting Met
ADCs are highly specific biopharmaceutical drugs composed of an antibody linked,
via a chemical linker, to a cytotoxic compound for targeted cancer therapy. A few anti-Met
ADCs have been designed, and they are currently in clinical investigation.
Telisotuzumab vedotin (ABBV-399) was designed by conjugating telisotuzumab (ABT-
700, anti-Met mAb) with monomethyl auristatin E (MMAE, a cytotoxic drug) via a cleavable
dipeptide linker [
44
]. It was shown to produce a potent anticancer effect against Met-
overexpressing cancer cell lines with either Met protein overexpression or MET gene
amplification. The specificity of ABBV-399 against Met-overexpressing cancer cells stems
from the fact that a threshold level of cell surface Met expression (
≥
100,000 Met molecules
per cell) is needed for the cells to experience the cytotoxic effect from the ADC [
44
]. Thus,

Drugs Drug Candidates 2023,2598
normal cells (including fibroblasts, endothelial cells, and non-cancerous epithelial cells)
that have a low cell surface expression of Met protein are insensitive to ABBV-399 [
44
].
In various Met-overexpressing xenograft tumor models
in vivo
, ABBV-399 was shown
to produce remarkable and durable tumor regression, and it also produced synergistic
antitumor effects with other chemotherapeutic drugs. Results from a recent phase 1 trial
for patients with advanced solid cancers (NCT02099058) showed that ABBV-399 was well-
tolerated, and it produced partial response (three out of sixteen patients) in a sixteen patient
Met-expressing NSCLC cohort [58].
SHR-A1403 is another ADC formed by conjugating the humanized anti-Met mono-
clonal antibody HTI-1066 with auristatin analog SHR152852 via a non-cleavable linker [
59
].
In animal studies, SHR-A1403 was shown to be stable, and free toxin was not detectable
in the serum [
60
]. It was shown to significantly retard xenograft tumor growth in various
animal models from different cancer types with Met overexpression [
59
,
60
]. SHR-A1403 is
currently being evaluated in a phase 1 clinical trial (NCT03856541).
TR1801-ADC is considered a “third generation” ADC generated by the site-specific
conjugation of the humanized monoclonal antibody hD12 to tesirine via a PBD toxin
linker [
61
]. Among all the anti-Met ADCs tested, TR1801-ADC was shown to be the most
cytotoxic in cancer cell lines expressing variable Met levels [
62
]. Importantly, TR1801-ADC
was also found to display a potent (at a single dose of 1 mg/kg) and long-lasting (up to
4 weeks) tumor-suppressive effect in a CRC-patient-derived tumor xenograft model [
61
].
Currently, TR1801-ADC is being investigated in a phase 1 trial (NCT03859752) in adult
patients with Met-overexpressing solid tumors.
B10v5x225-H-vc-MMAE and B10v5x225-M-vc-MMAE are two recently reported dual-
acting ADCs that target both Met and EGFR [
63
]. These bispecific antibodies were designed
by connecting optimized protein sequences specific to the EGFR epitope derived from the
EGFR mAb (cetuximab C225, with either a high or moderate binding affinity (therefore
termed 255-H and 255-M, respectively)) and another one specific to the Met SEMA domain
(termed B10v5, derived from a phage-displayed anti-Met mAb B10) [
63
]. On the other
hand, monomethyl auristatin E (MMAE) is a commonly used payload in ADC design.
Results from cell line studies showed that both B10v5x225-M and B10v5x225-H could
inhibit the ligand-induced receptor activation of Met and EGFR, thereby blocking MET
signaling and EGFR phosphorylation [
63
]. The two bispecific ADCs were shown to display
potent anticancer effects (with IC
50
ranging from 0.4 to 1 nM) in a panel of cancer cell lines
expressing various levels of Met and EGFR [63].
2.2. Inhibiting Met Dimerization
The dimerization of the Met receptor protein is known to be an essential signal
transduction mechanism regulating the HGF/Met pathway. DNA-based aptamers have
been designed to bind specifically to the extracellular domain of the Met receptor protein
and compete with HGF, thereby blocking Met dimerization [
64
,
65
]. Two representative
aptamer designs are described below. CLN0003_SL1 (abbreviated as SL1) is a 50-mer Met-
binding DNA aptamer, which was shown to work as a Met antagonist by competing with
HGF for Met binding [
66
,
67
]. SL1 exhibited high specificities and affinities to recombinant
and cellular-expressed Met. It inhibited HGF-dependent Met activation, the downstream
signaling pathway, and cancer cell migration. In a more recent study, Aida et al. reported
a photocleavable molecular glue,
PC
Glue-NBD, that could inhibit receptor dimerization
and subsequent activation [
68
]. The
PC
Glue-NBD molecule is a dendrimer with nine
guanidinium ion (Gu
+
) pendants, which form a multivalent salt bridge with the oxyanionic
groups on the target protein of interest. Moreover, there are photocleavable linkages on
the glue molecule. When it is subjected to UV irradiation, protein-bound
PC
Glue-NBD is
degraded and subsequently released from the protein. Using the HGF-Met axis as a proof-
of-concept demonstration, the interaction between HGF and Met could be blocked when
HGF was bound by
PC
Glue-NBD. However, upon exposure to UV light, the high-affinity

Drugs Drug Candidates 2023,2599
interaction between HGF and Met was restored to allow Met dimerization and activation
of the downstream signaling pathways [65].
2.3. Small-Molecule Met Tyrosine Kinase Inhibitors (TKIs)
The first crystal structure of Met kinase domain bound with the microbial alkaloid
K-252a was resolved in 2002 [
69
]. The availability of more crystal structures of Met kinase
bound to various small molecule inhibitors has facilitated the rational design of Met TKIs
capable of occupying the ATP pocket of the enzyme [
70
]. Underiner et al. compiled an
excellent review about the detailed structure–activity relationship evaluation of the pioneer
Met TKIs [71].
Numerous Met TKIs have been designed and developed in recent years [
72
]. They
can be classified as type Ia, Ib, II, and III according to their binding mode to the Met
tyrosine kinase domain [
73
]. The stage of their clinical investigation and approval status
is summarized in Table 1. There is a conserved region called the Asp-Phe-Gly (DFG)
motif at the N terminus of the activation loop of protein kinases including Met [
74
]. Upon
conformational change, the Met tyrosine kinase is switched from a catalytically active
state (“DFG-in” conformation) to an inactive state (“DFG-out” conformation) [
75
]. Both
type I and II Met TKIs are ATP-competitive inhibitors. More specifically, type I inhibitors
bind to the U-shaped ATP-binding pocket of the active “DFG-in” state through the M1160
residue by hydrogen bonding [
70
]. They also form
π
-
π
stacking interactions with the Y1230
residue within the activation loop and link with the hinge [
70
]. This makes type I Met TKIs
more selective than other types of Met TKIs. Type I Met TKIs can be further classified into
type Ia and Ib according to their binding to the solvent front glycine residue (G1163) on
the Met receptor. Type II Met TKIs are also ATP-competitive inhibitors. They bind to the
hydrophobic pocket of the inactive “DFG-out” state [
76
], which exerts an enzyme-inhibitory
effect by locking the molecule in the inactive state [
77
]. On the other hand, type III Met
TKIs are allosteric inhibitors that do not compete with ATP, and they were designed to
interact with the inactive Met conformation [78].
Table 1.
Representative Met TKIs approved or under clinical investigation for treating cancers with
MET dysregulation.
Type Name Molecular Target(s) * Approval Status (Indications) Representative Clinical Trials
Ia Crizotinib
(PF-02341066) ROS1 > Met > ALK
Approved (indicated for advanced
NSCLC with ALK or ROS1;
breakthrough therapy for advanced
NSCLC with MET exon 14 skipping
as second-line therapy)
Phase 1 (NCT00585195)—first-in-class
drug candidate demonstrating clinical
efficacy in NSCLC patients bearing
MET-exon-14-skipping mutations
Phase 2 (NCT02465060)
Phase 2 (NCT02499614)
Phase 2 (NCT02034981)
Ib
Capmatinib
(INCB28060) Met Approved (indicated for advanced
NSCLC with MET exon 14 skipping)
Phase 2 (NCT02414139, GEOMETRY
mono-1)—pivotal trial demonstrating
substantial antitumor efficacy of
capmatinib in NSCLC patients with
MET-exon-14-skipping mutations
Phase Ib/II
(NCT01610336)—combination with
geftinib
Phase Ib/II
(NCT02468661)—combination with
erlotinib
Tepotinib
(EMD1214063) Met Approved (breakthrough therapy for
advanced NSCLC with MET exon 14
skipping as first-line therapy)
Phase 2 (NCT02864992,
VISION)—pivotal trial demonstrating
favorable ORR and mPFS from tepotinib
in NSCLC patients with
MET-exon-14-skipping mutations
Phase Ib/II (NCT01982955,
INSIGHT)—combination with gefitinib
Phase II (NCT03940703, INSIGHT
2)—combination with osimertinib

Drugs Drug Candidates 2023,2600
Table 1. Cont.
Type Name Molecular Target(s) * Approval Status (Indications) Representative Clinical Trials
Savolitinib
(AZD6094, volitinib) Met Conditionally approved in China for
advanced NSCLC with MET exon 14
skipping mutations
Phase 2 (NCT02897479)—pivotal trial
demonstrating favorable clinical outcome
and safety profile from single-agent
savolitinib in Chinese patients with PSC,
brain metastasis, and NSCLC patients
with MET-exon-14-skipping mutations.
Savolitinib was conditionally approved
in China.
Phase Ib (NCT02143466, TATTON), Phase
2 (NCT03778229; SAVANNAH) and
Phase 2 (NCT03944772;
ORCHARD)—demonstrating clinical
efficacy of savolitinib–osimertinib
combination in acquired resistance
setting in advanced NSCLC with MET
alterations.
APL-101
(Bozitinib) Met Under clinical investigation Phase 1 (NCT03175224)
SAR125844 Met Under clinical investigation Phase 1/2 (NCT01391533)
Phase 2 (NCT02435121)
II
Cabozantinib
(XL-184, BMS-907351) VEGFR2 > Met > Ret > Kit >
Flt-1/2/3/4 > AXL > Tie2
Approved (indicated for renal cell
carcinoma and advanced metastatic
medullary thyroid carcinoma)
Phase 3 (NCT01865747)—cabozantinib
improved PFS compared to everolimus in
RCC patients who progressed after
VEGFR-targeted therapy
Phase 2 (NCT01639508)—cabozantinib
showing favorable clinical efficacy in
patients with RET-rearranged lung cancer
Merestinib
(LY2801653)
DDR1 > Met ~ AXL >
MKNK1/2 > FLT3 > DDR2 >
MERTK > MST1R > ROS1 Under clinical investigation Phase 1 (NCT03027284)
Phase 2 (NCT02711553)
Phase 2 (NCT02920996)
Glesatinib
(MGCD265) Met > RON > VEGFR1/2 /3 >
Tie-2 Under clinical investigation Phase 1 (NCT00697632)
Phase 2 (NCT02544633)
Sitravatinib
(MGCD516) TAM receptors (Axl, Mer) >
VEGFR2 > KIT > Met Under clinical investigation
Phase 2 (NCT03606174)—combination
with PD-1 checkpoint inhibitor
Phase 3 (NCT03906071)—combination
with PD-1 checkpoint inhibitor in
metastatic NSCLC
Altiratinib
(DCC-2701) Met > Tie2 > VEGFR2 Under clinical investigation Phase 1 (NCT02228811)
Foretinib
(GSK1363089) Met > AXL > RON > VEGFRs Product development terminated by
sponsor company in 2015
Phase 2 (NCT00726323)
Phase 2 (NCT02034097)—product
development terminated by sponsor
III Tivantinib
(ARQ197) Met > RON Under clinical investigation
Phase 2 (NCT00988741)
Phase 2 (NCT01892527)—combination
with cetuximab in resistant MET high
subjects
Phase 2 (NCT01519414)
Abbreviations: mPFS, median progression-free survival; NSCLC, non-small-cell lung cancer; ORR, objective
response rate; RCC, renal cell carcinoma. * The relative rank of target inhibition is shown according to Ki value in
cell-free or cell-based assays.
2.3.1. Type Ia Met TKIs
Crizotinib (PF-02341066) is an ATP-competitive multitargeted TKI inhibiting
Met/ALK/ROS1 [
79
]. A detailed structure-based drug design strategy and lead compound
optimization was reported by Cui et al. [
79
]. The structural backbone of 3-substituted
indolin-2-ones (known to be a potent class of kinase inhibitors, as exemplified by sunitinib)
was used in the search for lead compounds of novel Met TKIs. The cocrystal of PHA-665752
(analog of sunitinib) and Met complex revealed a novel binding model of Met, which was
subsequently used to guide both the lead candidate prioritization and further structural
optimization. A novel series of 2-amino-5-aryl-3-benzloxy-2-aminopyridine analogs was
generated, which were shown to interact with the ATP-binding pocket of Met with a bet-
ter ligand efficiency than PHA-665752. Further structural modification of the lead series
gave rise to crizotinib as a potent Met and ALK inhibitor [
79
]. In the Profile 1001 trial
(NCT00585195), crizotinib was the first-in-class drug candidate shown to exhibit clinical
efficacy in NSCLC patients bearing MET-exon-14-skipping mutations [
80
]. Among the
eighteen evaluable patients in the study, there were eight (44%) partial responses and
nine (50%) stable diseases. Importantly, none of the subjects exhibited progressive disease.
The drug-related adverse events were mostly grade 1 or 2. No grade 4 adverse event
was registered. After crizotinib therapy, the objective response rate (ORR) was 32%, and

Drugs Drug Candidates 2023,2601
the median progression-free survival (mPFS) was 7.3 months [
81
]. Following the Profile
1001 trial, crizotinib was granted a breakthrough therapy designation by the US Food and
Drug Administration (FDA) for the management of metastatic NSCLC patients bearing
MET exon 14 alterations who progressed after receiving platinum-based chemotherapy.
Moreover, crizotinib is also the first small-molecule TKI approved by FDA for the treatment
of ALK-mutated NSCLC [
82
]. Furthermore, crizotinib is currently also recommended by
the National Comprehensive Cancer Network (NCCN) for MET-mutated NSCLC [83].
2.3.2. Type Ib Met TKIs
Capmatinib and tepotinib are the first two types Ib Met TKIs approved by FDA
specifically for the treatment of metastatic NSCLC harboring MET-exon-14-skipping mu-
tations [
84
]. Capmatinib (INCB28060) and tepotinib (EMD1214063) are both orally ad-
ministered, selective, and highly potent Met TKIs with more than a 10,000-fold selectivity
over other major human kinases [
85
,
86
]. The approvals were based on the multi-cohort
phase II GEOMETRY mono-1 (capmatinib) [
87
] and VISION (tepotinib) studies [
88
]. In
the GEOMETRY study (NCT02414139), capmatinib displayed a substantial antitumor ef-
ficacy in advanced NSCLC patients with MET-exon-14-skipping mutations, particularly
in those not treated previously [
87
]. Interestingly, the clinical efficacy of capmatinib in
MET-amplified NSCLC patients was higher in tumors with a higher MET copy number
than those with a lower MET copy number [
87
]. In the VISION trial (NCT02864992),
NSCLC patients harboring MET-exon-14-skipping mutations were recruited according to
their liquid biopsy (DNA-based) or tissue biopsy (RNA-based) [
88
]. The ORR and mPFS of
all recruited patients were 46% and 11.1 months, respectively. The most common adverse
effects of tepotinib were an increase in blood creatinine and peripheral oedema, which
were all manageable. Due to its favorable clinical outcome, tepotinib was subsequently
approved in Japan for NSCLC patients with MET-exon-14-skipping mutations.
There are a few more type Ib Met TKIs currently under clinical investigation, (savoli-
tinib, APL-101, and SAR125844). Savolitinib (also known as AZD6094 and volitinib) is a
highly selective Met TKI that is conditionally approved in China for advanced NSCLC
with MET-exon-14-skipping mutations [
89
]. In a pivotal phase 2 trial (NCT02897479),
savolitinib as a monotherapy demonstrated notable clinical responses and a well-tolerated
safety profile in Chinese patients with pulmonary sarcomatoid carcinoma (PSC), brain
metastasis, and other NSCLC subtypes positive for MET exon 14 mutations [
90
]. The ORRs
of the PSC group and the NSCLC subtypes were 55% and 50%, respectively [
90
]. Moreover,
the combination of savolitinib and osimertinib has been evaluated in NSCLC patients
refractory to first- to third-generation EGFR TKIs, and it exhibited MET amplification or
Met immunohistochemistry (IHC) 3+ in a phase Ib TATTON study (NCT02143466). The
drug combination was found to achieve similar ORR and mPFS results in NSCLC patients
with or without EGFR T790M mutation (ORR of 67% and mPFS of 11.0 months versus
ORR of 65% and mPFS of 9.0 months, respectively). More recently, preliminary results
from ongoing phase 2 clinical studies (SAVANNAH study (NCT03778229) and ORCHARD
study (NCT03944772)) also confirmed the efficacy and safety of a savoltinib–osimertinib
combination in an acquired resistance setting in advanced NSCLC and its subtypes with
MET alterations [
91
,
92
]. A few phase 3 trials (NCT04923945 and NCT05261399) are ongoing
that are investigating the clinical efficacy of savolitinib for NSCLC patients harboring MET
exon 14 mutations or NSCLC patients whose disease progressed on osimertinib.
SAR125844 is a highly selective type Ib Met TKI that is administered intravenously [
93
]
that is being investigated in a phase 1/2 clinical study (NCT01391533). Preliminary findings
revealed that SAR125844 gave rise to a partial response (PR) and stable disease (SD) in five
and seventeen (out of twenty-two) NSCLC patients with MET amplification, whereas no
response was noted in patients with high-p-Met tumors [94].
PLB-1001 (also known as APL-101) is another potent and ATP-competitive type of
Ib Met TKI. In various preclinical models, it displayed remarkable anticancer potency by
selectively inhibiting MET-altered cancer cells [
95
]. In a phase 1 clinical trial (NCT03175224)

Drugs Drug Candidates 2023,2602
enrolling MET-altered chemo-resistant glioma patients, PLB-1001 was well-tolerated, and it
produced partial response in at least two advanced patients [96].
2.3.3. Type II Met TKIs
Numerous studies have reported that certain mutations near the active site of Met
could lead to resistance to type I Met TKIs [
97
]. Based on clinical experience with type I
Met TKIs, the response rates ranged from 32 to 55% and the median PFS achieved were
about 5–12 months [
81
,
98
–
101
]. Importantly, type I Met TKIs are limited by the inevitable
emergence of acquired drug resistance. To this end, type II Met TKIs do not rely on A-loop
interactions for binding to the kinase, but they recognize the inactivated conformation of
the Met activation loop (DFG-out). Therefore, type II Met TKIs are generally considered
more effective in killing cancer cells that possess the type I Met inhibitor resistance-causing
mutations because their binding interactions extend outside the Met active site [
97
,
102
–
107
].
On the other hand, due to the binding mode of type II Met TKIs with the targeted Met
kinase, they are considerably less selective than type I Met TKIs and therefore they are
associated with an increased risk of toxicity [108].
Cabozantinib (XL-184 or BMS-907351) is a type II Met inhibitor that was approved
by the FDA for the treatment of metastatic medullary thyroid cancer (November 2012),
renal cell carcinoma (April 2016), and hepatocellular carcinoma (January 2019). It inhibits
vascular endothelial growth factor receptor 2, Met, FMS-like tyrosine kinase 3, and Kit (stem
cell factor receptor). Cabozantinib and a few other type II Met TKIs were developed with a
6,7-disubstituted-4-(2-fluorophenoxy) quinoline backbone (Figure 3). Analysis of the
structure–activity relationships of quinoline-based Met inhibitors revealed that the
6,7-disubstituted-4-phenoxyquinoline backbone (moiety A) and an aryl fragment (moiety
B) formed hydrogen bonds and van der Waals interactions with Met kinase
[109–111]
. More-
over, moiety B fitted into the hydrophobic pocket. These 6,7-disubstituted-4-
phenoxyquinoline derivatives display two common structural features (5-atom regulation
and containing both hydrogen-bond donor and acceptor) within the linkers between the
two aromatic moieties (A and B) (Figure 3) [
112
–
114
]. Further structural modification with
a suitable linker may be pursued to develop new quinoline-based type II Met inhibitors.
Other type II Met inhibitors in clinical development include merestinib, glesatinib,
sitravatinib, and altiratinib. Merestinib (LY2801653) is a multi-kinase inhibitor that is effec-
tive against MET, MST1R, FLT3, AXL, MERTK, TEK, ROS1, NTRK1/2/3, and
DDR1/2 [
115
,
116
]. It is currently under investigation in an ongoing phase 2 study
(NCT02920996) for advanced NSCLC patients bearing MET exon 14 mutations or other
advanced cancer patients harboring an NTRK1/2/3 rearrangement. In a few case reports,
merestinib was shown to exhibit a promising antitumor activity in NSCLC patients with
the MET-exon-14-skipping mutation who did not respond to crizotinib or capmatinib [
117
].
Glesatinib (MGCD265) is another multi-kinase inhibitor targeting various oncogenes such
as MET, AXL, VEGFR1/2/3, RON, and TIE-2 [
118
,
119
]. In a recently published phase 1
clinical trial (NCT00697632), glesatinib was well-tolerated [
120
]. Antitumor activity was
observed following glesatinib therapy alone, with an ORR of 25.9% and 30.0% in cancer pa-
tients with MET/AXL mutations and MET-activating mutations, respectively. The findings
from this study have led to the initiation of another phase 2 study (NCT02544633) to investi-
gate the clinical efficacy of glesatinib in NSCLC patients stratified by different types of MET
alterations. On the other hand, glesatinib was also reported to exhibit efficacy in patients
with MET-exon-14-skipping mutations and acquired resistance to crizotinib [117,118].
Sitravatinib (MGCD516) is a broad-spectrum TKI targeting TAM receptors (TYRO3,
AXL, and MERTK), VEGFR2, c-Kit, and Met. These receptors regulate several immune-
suppressive cell types in the tumor microenvironment (including M2-polarized macrophages,
MDSCs, and T regulatory cells), which play a critical role in mediating resistance to the
immune checkpoint inhibitors in cancer immunotherapy [
121
]. Therefore, the combination
of sitravatinib and checkpoint inhibitors to augment antitumor efficacy has been actively

Drugs Drug Candidates 2023,2603
pursued in recent clinical trials [
122
,
123
]. Importantly, biomarker analyses in some of these
trials supported an immunostimulatory mechanism of action [122].
Figure 3.
Structural features of type II Met TKIs in various stages of development. The 6,7-
disubstituted-4-phenoxyquinoline core backbone (labelled as “moiety A”), which forms hydrogen
bonds and maintains van der Waals interactions with the ATP binding site of Met kinase, is high-
lighted in green dotted square. The other aryl fragment (labelled as “moiety B”), which fits into
the hydrophobic pocket of the receptor, is highlighted in blue bracket. The essential 5-atom linker
between moiety A and B is labelled in red.
Altiratinib (DCC-2701), a novel multi-kinase inhibitor, was designed to inhibit not only
the mechanism of tumor initiation and progression but also the drug resistance mechanisms
within the tumor microenvironment through the balanced inhibition of MET, TIE2, and
VEGFR2 kinases [
124
]. Its binding to the switch control pocket of all three kinases was
optimized, thus inducing type II inactive conformations [
124
]. Altiratinib was found to
inhibit both the wild-type and mutated forms of Met
in vitro
and
in vivo
. By inhibiting the
three oncogenic kinases (MET, TIE2, and VEGFR2), altiratinib was shown to inhibit the three
major vascularization and resistance signaling pathways (HGF, ANG, and VEGF), thereby
blocking tumor invasion and metastasis in preclinical tumor models [
124
,
125
]. However,
the phase 1 trial (NCT02228811) evaluating the safety of altiratinib was terminated by the
sponsor company in 2016.
Foretinib (GSK1363089) is another oral multi-kinase inhibitor known to target Met,
RON, AXL, and VEGFRs [
126
] that has also been extensively investigated in clinical trials.
While foretinib was originally designed as a Met TKI, it was later identified as a potent ROS1
inhibitor in an unbiased high-throughput kinase inhibitor screening assay [
127
]. Oncogenic
ROS1 signaling is activated by interchromosal translation or intrachromosomal deletion

Drugs Drug Candidates 2023,2604
that results in N-terminal ROS1 fusion genes that has been reported in a subset of patients
with glioblastoma, NSCLC, and cholangiocarcinoma [
128
]. In clinical practice, the two types
Ib Met TKIs (capmatinib and tepotinib) are indicated for the first-line treatment of NSCLC
bearing the MET-exon-14-skipping mutation (METex14). However, the emergence of
acquired resistance to capmatinib and tepotinib is almost inevitable, which is contributed to
mainly by the D1228X(N/H/Y/E) or Y1230X(C/H/N/S) secondary MET mutations [
129
].
A recent preclinical study was conducted to investigate whether six type II Met TKIs were
effective against both D1228X and Y1230X Met after the failure of capmetainib/tepotinib
in NSCLC patients with METex14 [
130
]. Importantly, only foretinib was found to exhibit
a potent inhibitory activity against both D1228X and Y1230X secondary MET mutations
in vitro
and
in vivo
[
130
]. Therefore, foretinib may be suitable for the second-line treatment
of NSCLC harboring METex14 after campatinib/tepotinib failure due to secondary D1228
or Y1230 mutations. About 10 phase 1/2 trials have been conducted for foretinib. However,
single-agent foretinib did not demonstrate notable clinical efficacy in unselected patients in
most studies [
131
]. In 2015, GlaxoSmithKline decided to terminate the product development
of foretinib. Despite the discontinuation of the development of foretinib, the TKI is still
commonly used as a control Met-targeting candidate during the investigation of a newer
generation of Met TKIs because of its unique structure and binding behavior.
2.3.4. Type III Met TKIs
Tivantinib (formerly known as ARQ197) represents a type III Met TKI that has
reached the most advanced stage of clinical investigation. It interacts with the inactive
non-phosphorylated configuration of Met and inhibits the autophosphorylation of the
kinase [
78
]. It is highly selective for Met (10- to 100-times more selective for Met than 229
other kinases tested) with an inhibitory constant (Ki) of 355 nM [
132
]. In preclinical studies,
tivantinib exhibited broad-spectrum anticancer effects in various cancer types, including
lung cancer, melanoma, breast cancer, colon cancer, ovarian cancer, gastric cancer, and
hepatocellular carcinoma [
133
]. It is noteworthy that tivantinib can also bind directly to
microtubules and disrupt microtubule function to induce mitotic catastrophe and apop-
tosis [
134
,
135
]. As tivantinib could inhibit cancer cell growth regardless of the cellular
activation status of Met, microtubule inhibition has been proposed to be the key mechanism
mediating the tivantinib-associated anticancer effect in hepatocellular carcinoma [
136
]. The
clinical efficacy of tivantinib has been evaluated in a few phase 2 and 3 trials for patients
with advanced Met-positive hepatocellular carcinoma. No substantial clinical benefit was
observed. Only in a phase 2 study (NCT00988741) was tivantinib shown to produce a
significantly longer PFS than a placebo (1.6 months versus 1.4 months; p= 0.04) [
137
].
However, there was no significant difference in the median PFS (tivantinib 1.5 months,
placebo 1.4 months; p= 0.06) and OS (tivantinib 6.6 months, placebo 6.2 months; p= 0.63)
between the tivantinib and placebo groups [137].
2.3.5. Novel Met TKIs with Distinct Binding Mode
Collie et al. recently screened a DNA-encoded chemical library against the isolated
kinase domains of the wild-type and D1228V acquired resistance mutant forms of Met [
138
].
One drug candidate (compound 1) that was capable of inhibiting both forms of the Met
kinase was selected for a more detailed investigation. Using X-ray crystallography, com-
pound 1 was shown to bind to the D1228V Met kinase in an unprecedented manner [
138
].
In the compound 1-D1228V Met cocrystal structure (crystal structure was deposited in the
Protein Data Bank with accession code 8ANS), the indazole group of compound 1 binds to
the hinge region of the kinase (i.e., the ATP-binding site), and the drug molecule extends
into the back pocket towards the
α
C helix [
138
]. While this binding drug conformation
is similar to a type II Met inhibitor, the conformation of the drug-bound Met kinase is
highly unusual. Specifically, the conserved DFG motif adopts an “out” conformation, but
the vacated DFG pocket is not occupied by the compound. Instead, it is occupied by the
rearranged
α
C helix of the kinase molecule. With the DGF motif in the “out” conformation,

Drugs Drug Candidates 2023,2605
the A-loop is largely disordered. Importantly, V1228 (the mutated residue known to render
Met kinase resistant to type I Met inhibitors) was shown to be around 15 Å from compound
1 in the cocrystal, obviously not playing any role in the compound interaction. Importantly,
the compound was also shown to be highly specific to Met kinase in a recombinant kinase
profiling assay. Moreover, the new compound was also shown to inhibit the dimerization
of the Met receptor in a cell-based assay using a time-resolved FRET assay [
138
]. Collec-
tively, these findings suggest a novel mode of Met inhibition by the new compound. The
new compound may be used to simultaneously target the wild-type and drug-resistant
D1228V mutant form of Met without inducing toxicity due to non-specific inhibition of the
whole kinome.
2.3.6. Met Inhibitors Derived from Natural Sources
While most of the Met inhibitors reported originated from a de novo drug design
and structural optimization, a few natural compounds were also found to exhibit a Met-
inhibitory effect. Dictamnine is a naturally occurring small-molecule furoquinoine alkaloid
isolated from the root bark of Dictamnus dasycarpus Turcz. Its Met-inhibitory activity has
been recently reported [
139
]. The binding mode of dictamnine with the crystal structure
of Met protein (4IWD) was predicted by Autodock [
140
]. It was later verified by a cellu-
lar thermal-shift assay (CETSA) and a drug-affinity-responsive target stability (DARTS)
assay [
139
]. Consistent with its attenuation of the PI3K/AKT/mTOR pathway, dictam-
nine was shown to exhibit a synergistic anticancer effect with gefitinib and osimertinib in
EGFR-TKI-resistant lung cancer cell lines [
139
]. Withaferin A (a steroidal lactone derived
from Withania somnifera) and carnosol (a naturally occurring phenolic diterpene found in
rosemary) were reported to target pancreatic cancer stem cells as novel Met inhibitors [
141
].
2.3.7. Met-Targeting PROTACs
Proteolysis-Targeting chimeras (PROTACs) are chimeric bifunctional molecules that
target a protein of interest for ubiquitination and degradation [
142
]. A typical PROTAC
molecule consists of a ligand capable of binding to an E3 ligase that is connected via a
linker to another ligand capable of binding to the target protein (Figure 4). Therefore,
PROTACs promote the ubiquitination and subsequent proteasome-mediated degradation
of the protein target. A salient feature of PROTACs is that they not only bind to but also
eliminate those protein targets even without a distinct functionality (i.e., “undruggable”
proteins and non-enzymatic proteins). While Met TKIs have been developed for nearly
20 years, their clinical efficacies and progress are modest. It has been suggested that a
kinase-independent function of Met may drive cancer growth and metastasis. Therefore,
the degradation of the Met protein may be more advantageous over the inhibition of the
Met kinase activity for cancer therapy.
Crew’s research group developed a Met-targeting PROTAC based on a type II inhibitor,
foretinib [
143
–
145
]. VHL and CRBN are two popular E3 ligases recruited by PROTACs to
induce protein ubiquitination and degradation. Met-targeting PROTACs utilizing either
VHL or CRBN E3 ligase were shown to induce the rapid degradation of Met protein
in a concentration- and time-dependent manner. It is noteworthy that exon-14-deleted
Met lacks the juxta membrane domain recruitment site (Y1003) for its endogenous E3
ligase. To this end, foretinib-based VHL PROTAC was shown to induce the degradation of
exon-14-deleted Met.
More recently, Sachkova et al. also reported the design, synthesis, and
in vitro
evalua-
tion of some other cabozantinib-based PROTACs to target Met for cancer treatment [
146
].
As described above, cabozantinib is a clinically approved type II Met inhibitor for the
treatment of medullary thyroid cancer, advanced renal cell carcinoma, and hepatocellular
carcinoma. Among the cabozantinib-based PROTAC molecules tested, two molecules
bearing a VHL-ligand as the E3-ligase-binding moiety and a 10- to 12-atom glycol-based
linker were found to be the most effective in degrading Met protein and eliciting anticancer
activity in Met-overexpressing breast cancer cells in the nanomolar range [146].

Drugs Drug Candidates 2023,2606
Figure 4.
Schematic diagram showing the general design of a Met-protein-targeting proteolysis-
targeting chimera (PROTAC). A typical PROTAC consists of a Met ligand connected to an E3 ligand
via a linker. Crizotinib (a type Ia Met TKI) has been used as the Met ligand to specifically recognize
the Met kinase in a recent novel design. The Met protein is brought to close proximity to the E3
ligase in the presence of the PROTAC, which is subsequently ubiquitinated (Ub) and subjected to
rapid degradation.
3. Repurposing of Non-Oncology Drug as Met Inhibitors
Drug repurposing refers to the application of clinically approved drugs with known
safety profiles and defined pharmacokinetic properties for new indications. It has emerged
as an attractive approach for the search of effective and durable cancer treatment. Compared
with the de novo development of novel drug candidates, drug repurposing represents
a time-saving and cost-efficient method that can dramatically reduce the risk of drug
development. Numerous systematic methods utilizing multi-omics analyses, molecular
docking, artificial intelligence, and machine learning techniques have been used to facilitate
the identification of repurposed drugs for cancer therapy [
147
]. A few recent attempts to
identify repurposed drugs involving Met inhibition are described below.
3.1. High-Content-Analysis (HCA)-Based Screening for Met Inhibitors
HCA is widely used in biological research to identify small molecules, peptides,
or RNAi that could alter cell phenotypes with the simultaneous readout of several pa-
rameters [
148
]. Oh et al. recently reported an HCA-based novel therapeutics screening
method for Met-addicted glioblastoma [
149
]. Tumor cells isolated from 12 patients with
glioblastoma were cultured ex vivo and subjected to high-content screening. Multiple
cellular parameters, including Met protein immunofluorescence, cell viability, apoptosis,
cell motility, and migration, were assessed. Intriguingly, the tumor cells derived from
one glioblastoma patient (PDC6) exhibited a distinctively high Met level, and they were
highly susceptible to the anticancer effect of Met inhibitors [
149
]. Subsequent genetic, im-
munoblot, and drug sensitivity characterizations of PDC6 cells confirmed that the specific
glioblastoma patient had Met overexpression, thus supporting the reliability of the screen-
ing platform. This method was subsequently expanded for use as a drug-repurposing
screen. The patient-derived tumor cells were treated with 60 clinically approved drug

Drugs Drug Candidates 2023,2607
candidates. The concentration–response results of the mean phosphorylated Met intensity
and relative AUC value were analyzed. As the positive controls, all the Met-targeting drugs
(including crizotinib, cabozantinib, foretinib, capamatinib, and SAIT301) were shown to
significantly decrease the phosphorylated Met (p-Met) protein level (fluorescent image
intensity). Intriguingly, the specific CDK4/6 inhibitor (abemaciclib), but not palbociclib
and ribociclib, was found to drastically suppress the p-Met intensity. Consistent with
this novel finding, subsequent large-scale drug sensitivity screening in 59 cancer cell lines
(classified as sensitive or resistant to crizotinib and cabozantinib) and 125 glioblastoma-
patient-derived cancer cells confirmed that abemaciclib response correlates well with the
response to known Met inhibitors [149].
3.2. In Silico Structure-Based Repurposing Screening for Met Inhibitors
Cutinho et al. recently reported a structure-based and in silico pharmacophore-
modeling approach to identify possible Met-targeting drug candidates for repurpos-
ing [150]. A structure-based pharmacophore model was built using the optimized crystal-
lographic structure of Met protein (PDB ID: 3LQ8). The pharmacophore model was then
screened with publicly available databases of natural compounds and the FDA approved
drug database. Drug molecules sharing similar pharmacophoric features as the control
Met TKIs (cabozantinib and foretinib) were then subjected to molecular docking for a
detailed examination of binding interactions and conformations at the enzyme binding
site. Two clinically approved drugs (bicalutamide—anti-androgenic drug; diphenidol
hydrochloride—anti-emetic drug) were identified as putative Met kinase inhibitors. The
capacity of the drug candidates to form hydrogen bonds with MET1160 appears to be es-
sential for them to potentially function as Met kinase inhibitors [
150
]. The highest-ranking
hits were also inspected by using various in silico techniques, including SwissADME
and pkCSM, to check their bioavailability and pharmacokinetic parameters, respectively.
Further experimental validation is pending.
3.3. Kinobeads Technology for Kinase Drug Repurposing
Klaeger et al. recently analyzed the cellular molecular targets of 243 clinically ap-
proved kinase drug candidates using chemical proteomics [
151
]. The kinobeads technology
was employed, where the tested kinase drug candidates were incubated with cellular
extracts containing endogenous full-length proteins harboring various posttranslational
modifications and in the presence of regulatory proteins and metabolites [
152
]. The assay
was conducted in a competition-binding format. The promiscuous kinase inhibitors were
immobilized on a bead to capture the cellular kinases in the lysates. The extent of the
binding was quantified by mass spectrometry after pulldown assays. The kinobead assay
has an additional advantage in that some non-kinase proteins can also be identified as
novel targets of clinical kinase inhibitors. Using this kinobead assay, Klaeger et al. showed
that the Met TKI cabozantinib could also potently inhibit the tyrosine kinase fusion product
FLT3-ITD [
151
]. Importantly, cell lines bearing the FLT3-ITD rearrangement but not the
wild-type AML cell lines were found to be sensitive to cabozantinib treatment. Cabozan-
tinib was also shown to remarkably inhibit the phosphorylation of the FLT3 downstream
target STAT5 and exhibited an antitumor efficacy in a tumor xenograft model
in vivo
[
151
].
It is noteworthy that clinical trials are underway to evaluate the safety and efficacy of
cabozantinib in cancer patients harboring the FLT3/ITD rearrangement (NCT04116541,
NCT03425201, and NCT01961765).
4. Combination of Met Inhibitors with Other Cancer Treatment Modalities to
Overcome Drug Resistance
4.1. Use of Met TKIs to Overcome Drug Resistance to EGFR-Targeted TKIs
MET dysregulation is a well-known mechanism that contributes to drug resistance to
targeted cancer therapies [
153
]. Met hyperactivation was reported to account for about 22%
of acquired resistance cases following first-generation EGFR-targeted therapy [
154
,
155
].

Drugs Drug Candidates 2023,2608
While EGFR-TKIs often induce on-target drug resistance mechanisms (i.e., the EGFR T790M
mutation), MET gene amplification represents the most frequent cause of bypass pathway
activation as an acquired resistance mechanism to EGFR-TKIs. MET amplification was
reported in up to 50% of cases after the failure of second-line osimertinib therapy [
156
]
or in 7–15% of cases after an insufficient clinical response from first line osimertinib treat-
ment [
157
]. MET amplification also represents an important mechanism of intrinsic drug
resistance to osimertinib [
158
]. MET amplification/hyperactivation leads to the persis-
tent activation of signaling pathways downstream of EGFR (including MAPK, STAT, and
PI3K-AKT signaling). Importantly, MET amplification was detected in resistant cancer cells
with or without other concomitant resistance mechanisms, including the loss of the T790M
mutation in patients refractory to previous EGFR-TKI therapy. In addition, MET exon
14 mutations are also known to be the key resistance mechanism to EGFR-TKI therapy [
159
].
As osimertinib is currently the standard treatment for NSCLC in the first-line setting,
extensive research has been conducted to find out an effective strategy for resistance circum-
vention. A few recent preclinical studies have reported the use of Met inhibitors (crizotinib
being the most-studied) to overcome osimertinib resistance in EGFR mutant NSCLC cell
lines harboring MET gene amplification [
160
,
161
]. The combination of crizotinib and os-
imertinib has also been investigated in clinical trials in NSCLC patients with acquired
resistance to osimertinib and MET amplification [
162
,
163
]. The interim results from a
multicenter, open-label, phase 1b TATTON trial also revealed an encouraging antitumor ef-
ficacy from the combination of osimertinib and savolitinib (a type Ib Met TKI) in advanced
NSCLC patients with MET-amplified tumors who had disease progression on a previous
EGFR TKI [
164
]. Following the favorable clinical outcome from the TATTON trial, a phase
2 SAVANNAH trial (NCT03778229) was initiated to evaluate the efficacy of osimertinib–
savolitinib in similar patient cohorts with prior osimertinib exposure. One of the cohorts
of the multi-arm clinical trial ORCHARD (NCT03944772) was also set out to evaluate the
osimertinib–savolitinib combination. More recently, a combination of tepotinib (another
type Ib Met TKI) and osimertinib is currently under evaluation in the open-label, multi-
center phase 2 INSIGHT 2 trial (NCT03940703) in patients with metastatic EGFR-mutant
NSCLC and acquired resistance to first-line osimertinib and MET amplification [165].
In another phase 1 (CHRYSALIS) trial, the combination of lazertinib (a third-generation
EGFR TKI) and amivantamab (a bi-specific antibody targeting both Met and EGFR) was
investigated in NSCLC patients who were chemotherapy-naïve but refractory to osimer-
tinib treatment [
166
,
167
]. While patients with a Met- or EGFR/Met-based mechanism of
resistance exhibited an ORR of 50%, the response rate was increased to 90% in a patient
subgroup (10 patients) with high EGFR/Met expression as observed by immunohistochem-
istry. Another ongoing CHRYSALIS-2 trial (NCT04077463) has included a patient cohort to
validate this exciting finding.
4.2. Use of Met Inhibitors to Potentiate Antitumor Response to Cancer Immunotherapy
Programmed cell death receptor-1 (PD-1) is an inhibitory checkpoint protein expressed
on immune cells, including activated T cells, B cells, and natural killer cells. Upon the
binding of PD-1 to its major ligand, PD-L1, expressed in tumor cells, the T-cell-mediated
cancer-killing effect by the host’s immunity is suppressed. Blockade of the PD-1/PD-
L1 interaction represents an effective immunotherapeutic strategy for cancer treatment.
However, the response rate to the PD-1/PD-L1 inhibitor is limited. Many patients do not
respond, whereas others cannot achieve a durable clinical response. Extensive research has
been conducted to search for novel strategies that can enhance anticancer immunity.
To this end, Met signaling is known to induce PD-L1 expression in cancer cells [
168
].
While this implies a reduced responsiveness of Met-driven cancers to PD-1/PD-L1 im-
munotherapy, there are limited reports in the literature demonstrating the efficacy of single-
agent immune checkpoint inhibitors in cancer patients with MET-amplified/hyperactive
tumors. A recent retrospective study was conducted to investigate the clinical efficacy of
a single-agent PD-1/PD-L1-directed immune checkpoint inhibitor in advanced NSCLC

Drugs Drug Candidates 2023,2609
patients bearing at least one oncogenic driver alteration [
169
]. The ORR in the Met sub-
group (16%) was considerably lower than in the other patient subgroups (KRAS: 26%;
BRAF: 24%; ROS1: 17%) [
169
]. Therefore, patients carrying actionable tumor alterations
are recommended to receive targeted therapy and chemotherapy before considering the
monotherapy of anti-PD-1/PD-L1 immunotherapy [169].
It is noteworthy that NSCLC patients bearing EGFR or ALK oncogenic mutations
tend to have minimal to no smoking history [
170
]. In contrast, NSCLC patients carrying
Met-driven tumors consist of a relatively greater proportion of smokers [
171
]. Therefore,
Met-driven NSCLC tumors are also likely to carry a higher tumor mutation burden [
172
].
Consistent with this observation, only a modest clinical benefit is usually observed in
Met-dependent NSCLC patients [
173
]. Importantly, numerous preclinical studies have
suggested that the concomitant inhibition of Met could potentiate the efficacy of PD-1/PD-
L1 immune checkpoint blockade [
174
,
175
]. It has been shown that IFN
γ
could induce PD-L1
expression more readily in MET-amplified tumors [175]. To this end, the Met TKI JNJ-605
and a specific Met-blocking antibody were shown to significantly impair the induction
of both PD-L1 and PD-L2 by IFN
γ
[
175
]. Intriguingly, IFN-stimulated PD-L1/PD-L2
expression was not reversed by Met inhibitors in cancer cells that were not amplified [
175
].
More recently, bispecific anti-Met/PD-1 antibodies (also called diabodies) have been
developed to potentiate the antitumor efficacy of anti-PD blockade cancer immunother-
apy [
176
]. On the one hand, these diabodies were demonstrated to suppress HGF-induced
cancer proliferation, migration, and invasion by preventing the binding of HGF to Met [
176
].
On the other hand, they were also able to stimulate T cell activation by blocking the PD-1
pathways. Interestingly, the diabodies with a higher Met-binding affinity (diabody-mp)
were shown to exhibit a greater antitumor effect than the corresponding diabodies with a
lower Met-binding affinity (diabody-pm) [176].
In fact, the combination of PD blockade therapy and Met inhibitors has been actively
pursued in numerous multicenter clinical trials (summarized in Table 2). In 2021, the
combination of nivolumab (an anti-PD-1 monoclonal antibody) and cabozantinib (type
II Met TKI) was approved by the FDA as first-line treatment for patients with advanced
renal cell carcinoma after a fast-track real-time oncology review. The antitumor efficacy of
the combination was primarily substantiated by the encouraging results from the phase 3
international multicenter CheckMate 9ER trial (NCT03141177) [177,178].
Table 2.
Recent representative clinical trials investigating the combination of PD-1/PD-L1 blockade
therapy and Met inhibitors (clinicaltrials.gov, accessed on 1 May 2023).
Combination Cancer Type clinicatrials.gov Identifier (Phase) Status
Cabozantinib (Met TKI) +
nivolumab (anti-PD-1 mAb)
versus
Sunitinib (multitargeted TKI)
Previously untreated advanced RCC NCT03141177
(Phase 3)
Completed; nivolumab + cabozantinib
had significant benefits over sunitinib
with respect to PFS and OS.
cabozantinib (Met TKI) +
Nivolumab (anti-PD-1 mAb)
with or without
ipilimumab (anti-CTLA mAb)
Metastatic genitourinary tumors NCT02496208
(Phase 1) Active, not recruiting
(last update posted 26 April 2023)
APL-101 (Met TKI) +
genolimzumab/nivolumab (anti-PD-1
mAb)
Locally advanced or metastatic HCC
or RCC NCT03655613
(Phase 1/2) Terminated (due to administrative
reasons; status update on 6 May 2022)
Capmatinib (Met TKI) +
pembrolizumab (anti-PD-1 mAb)
NSCLC with PD-L1 expression > 50%
and no EGFR mutation or ALK
rearrangement
NCT04139317
(Phase 2)
Terminated (due to toxicity in the
drug combination arm; status update
on 27 February 2023)
Cabozantinib (Met/VEGFR TKI) +
nivolumab (anti-PD-1 mAb) +
ipilimumab (anti-CTLA mAb) Metastatic soft-tissue sarcoma NCT04551430
(Phase 2) Active, not recruiting
(last update posted 31 March 2023)
Cabozantinib (Met/VEGFR TKI) +
nivolumab (anti-PD-1 mAb) Metastatic microsatellite-stable
colorectal cancer NCT04963283
(Phase 2) Recruiting
(last update posted 15 December 2022)
Cabozantinib (Met/VEGFR TKI) +
nivolumab (anti-PD-1 mAb) Advanced HCC who progressed upon
first-line therapy NCT05039736
(Phase 2)
Not yet recruiting
(estimated start date
24 February 2023)
Cabozantinib (Met/VEGFR TKI) +
ipilimumab (anti-CTLA-4 mAb) +
nivolumab (anti-PD-1 mAb) Refractory cutaneous melanoma NCT05200143
(Phase 2) Recruiting
(last update posted 13 June 2022)
Abbreviations: HCC, hepatocellular carcinoma; NSCLC, non-small-cell lung cancer; OS, overall survival; PFS,
progression-free survival; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor.

Drugs Drug Candidates 2023,2610
4.3. Use of Met TKIs to Overcome Drug Resistance to Chemotherapy
Although immunotherapy and targeted drugs are revolutionizing the treatment
paradigm for numerous cancer types, chemotherapy still retains a vital role in most cancer
patients. Classical chemotherapy suppresses cancer proliferation and reduces the tumor
burden by exerting cytotoxic effects. However, treatment relapse and chemotherapy resis-
tance are almost inevitable. Aberrant MET regulation is frequently observed in various
cancer types and is associated with poor prognosis. Constitutive MET signaling is known
to mediate chemoresistance by protecting cancer cells from apoptosis, promoting tumor
invasion, and facilitating the epithelial-to-mesenchymal transition. There are two excellent
review articles published by Wood et al. and To et al. about the role of MET in chemoresis-
tance and the application of Met inhibitors to overcome drug resistance [179,180].
In preclinical studies, the HGF expression level was found to be higher in chemoresis-
tant cancer cells than their chemosensitive counterparts [
181
–
183
]. HGF overexpression
was shown to activate MET signaling in an autocrine manner, which increased basal Met
phosphorylation to promote cancer cell survival. In addition, HGF secreted from cancer-
associated fibroblasts has been reported to protect breast, glioblastoma, lung, and ovarian
cancer against classical chemotherapeutic-drug (camptothecin, cisplatin, and doxorubicin)-
induced apoptosis [
184
]. Moreover, dysregulated HGF/Met signaling could also activate
various downstream effectors including the cellular Src kinase (c-Src), phosphotidylinsitol-
3-OH kinase (PI3K), serine/threonine protein kinase (Akt), mitogen-activated protein
kinase (MAPK), and the Wnt/
β
-catenin pathway to promote cell proliferation, invasive-
ness, morphogenesis, and angiogenesis. The application of Met inhibitors to overcome
chemoresistance has also been investigated in clinical studies. Table 3summarizes the repre-
sentative clinical studies investigating the potentiation of chemotherapy by
Met inhibition
.
Table 3.
Representative clinical trials investigating the combination of Met inhibitors and classical
chemotherapeutic drugs.
Combination Cancer Type ClinicaTrials.gov
Identifier (Phase) Key Findings/Current Trial Status
Tivantinib (Met inhibitor) +
cetuximab (EGFR mAb) +
irinotecan (topoisomerase I
inhibitor)
CRC NCT01075048
(Phase 2)
•No significant difference in PFS between the two
treatment groups with or without tivantinib.
•Patient subgroup analysis revealed a better outcome in
patients with MET-high tumors, but subgroup patient
size was too small to draw conclusions.
Onartuzumab (anti-Met mAb) +
FOLFOX +
bevacizumab (anti-VEGF mAb) CRC NCT01418222
(Phase 2)
•No significant difference in PFS between the two
treatment groups with or without onartuzumab.
•Met immunohistochemistry was not a predictive
biomarker for treatment outcome.
Rilotumumab (anti-HGF mAb) +
epirubicin +
Cisplatin +
capecitabine
Gastric cancer NCT00719550
(Phase 2)
•Modest improvement in PFS in rilotumumab
combination over placebo (PFS: rilotumumab
combination, 5.7 months vs cytotoxic drugs without
rilotumumab, 4.2 months (HR, 0.60; p= 0.016)).
Rilotumumab (anti-HGF mAb) +
mitoxantrone +
prednisone
Castration-resistant prostate
cancer who had received
previous taxane chemotherapy
NCT00770848
(Phase 2)
•No significant PFS difference between rilotumumab
combination over cytotoxic drugs combination.
•Unfavorable OS associated with patients with high
tumor Met expression regardless of treatment.
Crizotinib (Met/ALK inhibitor) +
cyclophosphamide +
topotecan
Refractory solid tumors or
nnaplastic large-cell lymphoma NCT01606878
(Phase 1)
•Patients experienced increased toxicity in combination
treatment that was not explained by the relative
bioavailability or exposure.
Cabozantinib (Met/VEGFR
inhibitor) +
topotecan +
cyclophosphamide
Refractory Ewing sarcoma or
osteosarcoma NCT04661852
(Phase 1)
•Trial completed on 24 October 2022.
Cabozantinib (Met/VEGFR
inhibitor) +
cisplatin / doxorubicin /
methotrexate
Newly diagnosed osteosarcoma NCT05691478
(Phase 2/3)
•Suspended (scheduled interim monitoring as of 26
April 2023).
Abbreviations: CRC, colorectal cancer; FOLFOX, chemotherapeutic regimen consists of leucovorin, fluorouracil,
and oxaliplatin; HCC, hepatocellular carcinoma; PFS, progression-free survival; OS, overall survival.

Drugs Drug Candidates 2023,2611
5. Inherent and Acquired Resistance to Met TKIs
5.1. Inherent Resistance to Met TKIs
While cancer patients are selected to receive personalized therapy with Met TKIs
using a relevant MET-activation biomarker such as the MET-exon-14-skipping mutation,
the presence of other concurrent oncogenic driver mutations in the Ras-Raf-MAPK or
PI3K/Akt pathways are known to reduce drug sensitivity to Met TKIs [
185
,
186
]. In fact, it
has been reported that treatment-naïve NSCLC patients bearing the MET-exon-14-skipping
mutation did not respond to Met TKIs if they also have other oncogenic RAS or PI3K
mutations [
186
,
187
]. The hyperactive RAS or PI3K may be the driver oncogenes in the
tumors of those patients.
5.2. Acquired Resistance to Met TKIs
5.2.1. On-Target Resistance Mechanisms
Similar to other oncogene-targeted therapies, cancer cells could acquire resistance to
Met TKIs following drug treatment via either on-target or off-target mechanisms. Employ-
ing the Ba/F3 cell model expressing MET exon 14 alterations, Fujino et al. evaluated various
specific secondary mutations as resistance mechanisms to different types of Met TKIs [
188
].
As expected, mutations of D1228 and Y1230 in the Met kinase activation loop (A-loop) were
found to confer resistance to type I Met TKIs by disrupting the drug binding. On the other
hand, mutations of L1195 and F1200 outside the A-loop could mediate resistance to type II
Met TKIs. In addition, a few specific mutations including D1228A/Y were found to confer
resistance to both type I and II Met TKIs in the Ba/F3 cell model [
188
]. Interestingly, the two
sets of mutations (D1228/Y1230 and L1195/F1200) appear to be complementary to each
other. Type II Met TKIs were shown to overcome acquired resistance due to the secondary
mutations (D1228/Y1230) caused by type I Met TKIs and vice versa [
188
]. Indeed, this
secondary mutation complementarity was supported by clinical findings that glesatinib
(type II Met TKI) could overcome resistance due to Y1230H/S induced by prior crizotinib
treatment (type Ia Met TKI) [
118
]. Similarly, merestinib (type II Met TKI) maintained
antitumor activity against D1228N, which occurred after prior capmatinib treatment (type
Ib Met TKI) [117].
In a clinical setting, Recondo et al. recently compared paired pre- and post-Met TKI tu-
mor specimens from twenty NSCLC patients with MET-exon-14-skipping mutations [
117
].
The on-target (secondary mutations) and off-target (to be discussed below) resistance mech-
anisms were present in 35% and 45% of the patients, respectively [
117
]. Some patients
acquired both on-and off-target resistance mechanisms [
117
]. Consistent with the aforemen-
tioned Ba/F3 cell line study, D1228/Y1230 secondary mutations were primarily induced
after treatment with type I Met TKIs (crizotinib, capmatinib, and glesatinib). It is also
noteworthy that multiple secondary mutations could occur simultaneously in one patient,
thus pinpointing the heterogeneity in the Met TKI resistance mechanisms [
117
,
118
]. It may
be difficult to treat patients according to the resistance mechanism(s) identified from a
single biopsied tumor lesion because different secondary mutations may be operating in
other tumor lesions. In other clinical studies, high-grade MET and HGF gene amplifications
have also been reported as on-target mechanisms to mediate Met TKI resistance, respec-
tively [
117
,
187
]. Most recently, switching between different types of Met TKIs
(type I and II)
was shown to provide repeated clinical responses in cases with second-site mutations in
NSCLC patients bearing the MET-exon-14-skipping mutation [189].
5.2.2. Off-Target Resistance Mechanism
As with inherent resistance to Met TKIs, concomitant mutations in other parallels
(EGFR, HER3, KIT) or downstream signaling pathways (Ras/Raf/MAPK and PI3K/AKT)
were reported to contribute to acquired resistance to Met TKIs [
185
,
187
,
190
,
191
]. However,
it remains elusive as to whether there were tumor clones bearing these co-driver muta-
tions prior to Met TKI therapy or the tumor acquired these co-driver mutations during
the therapy.

Drugs Drug Candidates 2023,2612
In a recent study evaluating the role of aberrant PI3K regulation in Met TKI resistance,
NSCLC patients bearing PI3KCA mutations and PTEN loss were shown to be refractory
to Met TKIs [
186
]. To this end, PI3K inhibition was found to restore Met TKI sensitivity
in MET-exon-14-mutated cell lines with PI3K alteration, thus suggesting the ability of
the respective drug combination to overcome resistance. MET-exon-14-mutated cell lines
with Ras/MAPK pathway dysregulation (Kras overexpression or NF1 downregulation)
were also found to be resistant to Met TKIs, which could be reversed by a combination of
crizotinib and the MEK inhibitor trametinib [192].
6. Further Perspectives
MET dysregulation is a well-established oncogenic mechanism driving cancer devel-
opment, and it also mediates drug resistance to classical chemotherapy, targeted therapy,
and immunotherapy in the treatment of cancer. Accumulating preclinical evidence suggests
that MET is a druggable target for the circumvention of drug resistance [
153
,
179
]. The
combination of EGFR and Met inhibitors in clinical settings has been proposed to overcome
drug resistance because MET amplification is common in EGFR-mutated NSCLC patients
not responding to EGFR-targeted therapies [
156
,
193
,
194
]. However, early attempts in clin-
ics to investigate Met-targeted therapies in unselected cancer patients generally produced
disappointing results. In recent years, by stratifying cancer patients with specific MET
exon 14 alterations and MET amplification, more promising treatment outcomes following
treatment with Met inhibitors were observed. Therefore, the combination of Met inhibitors
with other cancer treatment modalities for the circumvention of drug resistance in a per-
sonalized manner has been advocated for [
147
]. It follows that robust and standardized
methods will be needed to evaluate the specific MET alterations in tumor specimens both
at diagnosis and at relapse.
It is commonly believed that the failure of the early clinical trials investigating Met-
targeting drugs could have resulted from lack of or inappropriate patient selection. In the
early trials, patient selection was based on Met expression in tumor specimens. Although
Met protein overexpression represents the most common manifestation of MET dysregula-
tion in NSCLC, it was not proven to be an effective biomarker to predict clinical response
to Met inhibitors in most cases [
195
]. The association between Met protein overexpression
and its activation is not very clear [195]. Therefore, the measurement of Met protein phos-
phorylation (p-Met) at tyrosine 1234/1235 may be more appropriate in reflecting the status
of MET activation. Indeed, only a fraction of Met-protein-overexpressing tumors actually
expressed the activated p-Met form [
196
]. To our knowledge, all clinical trials employing
immunohistochemical methods for the assessment of Met protein overexpression and
patient stratification did not produce a favorable clinical outcome for the Met-targeting
therapies under investigation [
197
]. Moreover, the detection of the phosphorylated form
of the protein (p-Met) is technically demanding [
198
]. Met phosphorylation could be
lost during specimen processing and during the immunohistochemical (IHC) staining
protocol [
198
]. Another critical drawback of using IHC for identifying tumors with MET
dysregulation was further demonstrated by a recent study conducted by the Lung Cancer
Mutation Consortium [
187
]. In this study, the correlation between MET amplification/MET
exon 14 alterations and Met protein IHC intensity was examined in tumor specimens from
181 patients with Met-IHC-positive NSCLC. Surprisingly, almost all Met-IHC-positive cases
were revealed to be negative for MET amplification or MET exon 14 alterations [187].
Therefore, instead of relying on the measurement of Met protein expression, the
identification of MET amplification or MET-exon-14-skipping mutations is currently recom-
mended as the preferred patient stratification strategy for the investigation of MET-targeted
therapies in NSCLC [
20
,
171
,
199
,
200
]. To this end, the cutoff value for defining clinically
relevant MET amplification in tumor specimens remains controversial. It has been pro-
posed that only the amplification of the MET locus represents a bona fide oncogenic event,
which is defined by a high ratio of MET to centromere 7 [
201
]. Meanwhile, the detection of
MET-exon-14-skipping alterations in circulating tumor DNA has been employed as a novel

Drugs Drug Candidates 2023,2613
patient selection strategy [
198
,
201
]. A companion diagnostic test, called FoundationOne
®
CDX, has been recently approved to select NSCLC patients with MET-exon-14-skipping
mutations for capmatinib therapy [
202
]. Nevertheless, it is noteworthy that the preva-
lence of MET-exon-14-skipping mutations is low, with rates of up to 4% being observed in
NSCLC [
203
]. Given that Met inhibitors are mostly multitargeted TKIs, the selection of a
small subpopulation of patients may miss some potential responders [204].
MET dysregulation is known to mediate resistance to classical chemotherapy, targeted
therapy, and immunotherapy. The combination of Met inhibitors and other cancer treatment
modalities is considered a rational strategy to overcome drug resistance. Given the limited
efficacy of PD-1/PD-L1 immunocheckpoint inhibitors in MET-dependent NSCLC, the use
of immunotherapy alone should be avoided. However, the results from a recent phase
1/2 clinical trial (CheckMate 370) investigating a combination of nivolumab (PD-1 inhibitor)
and crizotinib (Met/ALK inhibitor) raised toxicity concerns [
32
]. More investigation into
the combination of Met inhibitors and immunotherapy is warranted.
Similar to other targeted therapeutic drugs, acquired resistance to Met TKIs is almost
inevitable. The development of effective strategies to overcome Met TKI resistance is
needed to fully unleash the utility of this unique drug class. In both preclinical and clinical
studies, MET D1228 and Y1230 have been reported as hotspots for the secondary resistant
mutations for type I Met TKIs in NSCLC harboring MET-exon-14-skipping mutation.
Switching from the type I to type II Met TKI may represent an effective strategy to overcome
the D1228/Y1230-mutation-mediated resistance. However, a recent clinical case report
revealed that cabozantinib (type II Met TKI) could only eliminate the Y1230C mutant but
left behind the D1228N/Y/H mutant alleles [
205
]. In another clinical study about the
sequential treatment of type I and type II Met TKIs for MET-dependent NSCLC patients
harboring D1228X and Y1230X, only the D1228X mutant was detected in the tumor biopsies
at the time of disease progression [
206
]. Therefore, MET D1228X appears to be more
resistant than Y1230X to the currently available type II Met TKIs. The development of novel
Met TKIs could focus on drug candidates that are effective against the D1228X secondary
resistance mutant.
Author Contributions: Conceptualization, K.K.-W.T., K.-S.L. and W.C.-S.C.; writing—original draft
preparation, K.K.-W.T.; writing—review and editing, K.K.-W.T., K.-S.L. and W.C.-S.C.; supervision,
K.K.-W.T.; project administration, K.K.-W.T. and W.C.-S.C. All authors have read and agreed to the
published version of the manuscript.
Funding:
This work was supported by a research grant from Food and Health Bureau, HKSAR
(Health and Medical Research Fund 08190616).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments:
We thank all researchers who have contributed to this research area, but their
works are not included due to page limitations of the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
Activation loop (A-loop); antibody-dependent cell-mediated cytotoxicity (ADCC); antibody–
drug conjugate (ADC); acute myeloid leukemia (AML); disease control rate (DCR); epidermal growth
factor receptor (EGFR); epithelial-to-mesenchymal transition (EMT); hepatocyte growth factor (HGF);
high-content analysis (HCA); immunohistochemistry (IHC); leucine-rich repeats (LRR); monoclonal
antibody (mAb); monomethyl auristatin E (MMAE); non-small-cell lung cancer (NSCLC); objective
response rate (ORR); overall survival (OS); partial response (PR); programmed cell death receptor-1
(PD-1); progression-free survival (PFS); proteolysis-targeting chimerics (PROTACs); receptor ty-
rosine kinase (RTK); scatter factor (SF); stable disease (SD); tumor-associated macrophage (TAM);

Drugs Drug Candidates 2023,2614
ubiquitinated (Ub); tyrosine kinase inhibitor (TKI); vascular endothelial growth factor (VEGF); von
Hippel–Lindau protein (VHL).
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