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Mutational evolution of different molecular subtypes of uveal melanoma. An initial event, common to all tumor groups, is represented by GNAQ or GNA11 or CYSLTR2 or PLCB4 mutations determining constitutive MAPK activation. After this initial event, a first major branching determines the formation of two branches: one characterized by chromosome 3 disomy, and the other by chromosome 3 monosomy and BAP1 mutations. The subsequent sub-branching of the 3 disomy branch into sub-branches 1 and 2 is dictated by the acquisition of EIF1AX or SF3B1 mutations, respectively. The sub-branching of the 3 monosomy branch into sub-branches 3 and 4 is dependent upon the level of acquisition of a chromosome 8q gain, low in sub-branch 3 and high in sub-branch 4.
Source publication
Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are...
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Context 1
... studies have explored the genetic abnormalities observed in uveal melanomas, providing evidence that these tumors have a pattern of genetic abnormalities markedly different compared to those observed in cutaneous melanomas. Uveal melanoma is a malignant tumor originating from melanocytes of the choroid plexus, ciliary body, and iris of the eye, and represents the most common intraocular tumor in adults. It represents 3.1% of all melanomas, has an aggressive clinical course, is frequently metastatic, and is associated with poor survival (only 10-15% of patients survive at 1 year). In contrast to cutaneous melanomas, uveal melanomas lack mutations in BRAF, NRAS, and Kit genes, possess typical chromosomic abnormalities, and have a very pronounced tendency to metastasize at the level of the liver. Recent studies have shown the occurrence of some frequent and typical mutations in uveal melanoma. Thus, frequent somatic mutations in the heterotrimeric G protein ?- subunit, GNAQ, have been reported in 83% of blue naevi (intradermal melanocytic proliferations forming discrete bluish moles) and 46% of ocular melanomas of the uvea [127]. The GNAQ mutation occurs at the level of codon 209 in the Ras-like domain and determines the constitutive activation of this protein and, consequently, of the MAPK pathway (Table 3) [127]. Interestingly, a GNAQ mutation was observed in 6% of patients with naevus of Ota, a condition predisposing to the development of uveal melanoma in which a proliferation of intradermal melanocytes gives rise to hyperpigmentation of the conjunctiva and periorbital skin. Mutant GNAQ drives uveal melanoma development, activating various downstream signaling pathways, including Rho/Rac, YAP, and PLC/PKC. In this complex signaling pathway, a key role is played by the GTPase ADP-Ribosylation Factor 6 (ARF6) which acts as an initial target of GNAQ, coordinating the activation of all these signaling pathways and also inducing the activation of ?-catenin signaling [127]. ARF6 acts as a coordinator of all these pathways by a common mechanism involving the trafficking of both GNAQ and ?-catenin from the cell membrane to cytoplasmic vesicles and the nucleus [128]. In line with these observations, the pharmacological blocking of ARF6 function with a small-molecule inhibitor induced an inhibitory effect on the proliferation of uveal melanoma cells and of tumorigenesis in a model of uveal melanoma, thus supporting the functional relevance of this pathway and suggesting its possible targeting at a therapeutic level [128]. Another study carried out by the same investigators showed frequent mutations in uveal melanoma of the gene GNA11, encoding for a GNAQ paralogue. Mutations affecting the residue Q209 (glutamine is mutated either to proline or leucine) were present in 7% of blue naevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases (Table 3). The incidence of Q209 mutations in GNAQ was 55% in blue naevi, 45% in uveal melanomas, and 22% in uveal melanoma metastases [129]. In addition to Q209 mutations, more rarely somatic mutations in exon 4 (affecting R183) have been observed both in GNA11 and GNAQ genes: these mutations are mutually exclusive from those occurring at Q209 [129]. These mutations in GNA11 determine a constitutive activation of the MAPK pathway and induce the formation of spontaneously metastasizing tumors in suitable mouse models [129]. The conclusion of these studies was that more than 80% of uveal melanomas had somatic mutations in GNAQ or GNA11, implying that MAPK activation is a major contributor to the development of uveal melanoma. A molecular classification of uveal melanoma was currently reported and adopted for the identification of this tumor into two different risk classes: class I associated with a low risk of metastasis, and class II associated with high risk of metastasis. Among the various prognostic criteria, the monosomy of chromosome 3 strongly associates with class II tumors. According to these findings, Harbour et al. identified frequent mutations of the gene encoding BAP1 located on chromosome 3p21.1, occurring in 86% of class II uveal melanomas, but only in <5% of class I uveal melanomas (Figure 3) [130]. Most BAP1 gene mutations corresponded to premature stop codons; therefore, it is not surprising that BAP1 protein levels were markedly lower in class II tumors compared to those observed in class I tumors [130]. It is of interest to note that a minority of uveal melanoma patients exhibited germline BAP1 mutations, suggesting a possible role of mutations of this gene as a genetic factor predisposing to cancer development. In line with this hypothesis, a novel autosomal dominant syndrome was recently reported in two families that is caused by germline mutations of BAP1; it is characterized by a high penetrance of melanocytic tumors with peculiar clinical and histopathological feature, associated with an increased risk of uveal melanoma [131]. These observations were also confirmed by the analysis of families with the predisposition to develop uveal melanoma: in these families, a germline truncating mutation in the BAP1 gene was observed; in these cases, the development of uveal melanoma was associated with the concomitant development of another tumor-either meningioma, lung cancer, or neuroendocrine carcinoma [132]. According to all of these findings, a mutational model of uveal carcinoma was developed. This model implies that the initiating event is represented by an activating mutation occurring in a uveal melanocyte cell and acting via induction of the cell cycling triggered by constitutive MAPK activation. In most cases, the mutant clone does not progress and is either eliminated by apoptosis or gives rise to a benign nevus. More rarely, the initial clone progresses due to the accumulation of additional genetic abnormalities either along a low- risk or a high-risk melanoma, depending on the type of mutations accumulated [133]. This model of uveal melanoma development was supported by a recent study of whole-genome sequencing of uveal melanomas [134]. Unsupervised hierarchical clustering of uveal melanoma samples based on the analysis of copy number alterations showed the existence of four subgroups, from A to D [134]. Groups A and B involved tumors displaying chromosome 3 monosomy, chromosome 8q gain, and in some cases, chromosome 8p loss; group B tumors also had loss of chromosome 6q; groups C and D displayed less chromosome abnormalities, with group C tumors not showing major aneuploidies and group D displaying gains of the distal segment of chromosome 8q [134]. Tumors displaying chromosome 3 monosomy were associated with BAP1 mutations (77% of cases), while SF3B1 and EIF1AX mutations were observed among tumors C and D [133]. Considering the hallmark driver mutations in the GNAQ and GNA11 paralogs were observed in 100% of cases, a model of tumor evolution based on genetic mutational events progressively occurring in all the four tumor subgroups is provided (Figure 4 Risk of metastatic disease and survival is strongly associated with the molecular features of the tumor. Particularly, the status of chromosome 3 allows two prognostically different uveal melanoma groups to be distinguished: (a) metastatic disease strongly associated with chromosome 3 monosomy; (b) non-metastatic disease associated with disomy of chromosome 3 [131]. Recent studies showed the presence of recurrent mutations of the EIF1AX and SF3B1 genes preferentially associated with chromosome 3 disomy; in fact, in a group of uveal melanoma patients with chromosome 3 disomy, the frequency of EIF1AX (48%) and SF3B1 (29%) was clearly higher than in patients with chromosome 3 monosomy, where EIF1AX and SFB31 mutations together exhibited a frequency of 5.7% (Table 3) [135]. In contrast, patients with partial chromosome 3 monosomy-who usually have good prognosis-have uveal melanomas more similar to those with chromosome 3 disomy. In fact, 8% of these patients displayed EIF1AX mutations and 54% SF3B1 mutations [136]. Sequencing of SF3B1 and EIF1AX in ten uveal melanomas with disomy 3 who developed metastases showed that none of them displayed EIF1AX mutations, while 30% harbored a mutation in SF3B1 [136]. At the structural level, all EIF1AX mutations caused in-frame changes affecting the N-terminus of the protein, whereas the large majority of SF3B1 mutations affected an alteration of Arg 625 [136]. The findings concerning the SF3B1 gene were independently confirmed in another study showing that mutations of this gene are observed in low-grade uveal melanomas associated with good prognosis ...
Citations
... Genetic alterations in melanoma patients were seen to activate the RAS/RAF/MEK/ERK (MAPK) and the PI3K/PTEN/AKT (AKT) signaling pathways, so that it has been found that the growth of melanoma cells can be blocked as a result of inhibiting both ERK and PI3K signaling [11][12][13]. The MAPK (Mitogen-activated protein kinase) pathway can affect downstream pathways of some receptors, such as cytokine, heterotrimeric G-protein, and tyrosine kinase receptors. ...
... On the other hand, it is of note that rampant genetic changes in melanoma are capable of reducing apoptosis through the overexpression of B-cell lymphoma 2 (Bcl-2), loss of both Phosphatase and tensin homolog (PTEN) and nuclear factor-κB (NF-κB), and mutation of Akt3, NRAS, and BRAF [11,20]. Most importantly, lymphocytes and pigmented melanophages (possessing ingested melanin) are found close to the dermal-epidermal p53-positive cells, suggesting cell death among the melanocytes [21,22]. ...
Melanoma is the most aggressive form of skin cancer resulting from genetic mutations in melanocytes. Several factors have been considered to be involved in melanoma progression, including genetic alteration, processes of damaged DNA repair, and changes in mechanisms of cell growth and proliferation. Epigenetics is the other factor with a crucial role in melanoma development. Epigenetic changes have become novel targets for treating patients suffering from melanoma. These changes can alter the expression of microRNAs and their interaction with target genes, which involves cell growth, differentiation, or even death. Given these circumstances, we conducted the present review to discuss the melanoma risk factors and represent the current knowledge about the factors related to its etiopathogenesis. Moreover, various epigenetic pathways, which are involved in melanoma progression, treatment, and chemo-resistance, as well as employed epigenetic factors as a solution to the problems, will be discussed in detail.
... Malignant melanoma is among the most dangerous tumors due to its high probability of metastasizing and its increasing incidence year after year [136]. Currently, 75% of skin cancer deaths are due to melanoma [137]. There are three types of skin tumors: Melanoma, Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC). ...
Melanoma is considered a multifactorial disease etiologically divided into melanomas related to sun exposure and those that are not, but also based on their mutational signatures, anatomic site, and epidemiology. The incidence of melanoma skin cancer has been increasing over the past decades with 132,000 cases occurring globally each year. Marine organisms have been shown to be an excellent source of natural compounds with possible bioactivities for human health applications. In this review, we report marine compounds from micro- and macro-organisms with activities in vitro and in vivo against melanoma, including the compound Marizomib, isolated from a marine bacterium, currently in phase III clinical trials for melanoma. When available, we also report active concentrations, cellular targets and mechanisms of action of the mentioned molecules. In addition, compounds used for UV protection and melanoma prevention from marine sources are discussed. This paper gives an overview of promising marine molecules which can be studied more deeply before clinical trials in the near future.
... These congenital nevi are categorized based on size into small, medium, and large or giant [20], showing a consistent relation between nevus size and mutation status [21]. The most commonly mutated gene in congenital nevi is NRAS, although BRAF mutations can also be present but at very low frequencies and only in small congenital nevi [21,22]. Usually there is no overlap regarding mutations in both NRAS and BRAF. ...
... Therefore, as seen in CM, simultaneous mutations in both of those two genes are extremely rare, both in nevi and in CM. Mutations in other genes frequently altered in CM (TP53, CDKN2A, CDK4) have not been detected in congenital nevi [21,22]. ...
... Genetic analyses carried out in acquired nevi have revealed a low mutation burden in nevi compared to CM and have highlighted the recurrent mutations affecting codon 600 in BRAF (around 80%) or NRAS (20%) in this type of nevi [19,22,24]. Either BRAF or NRAS are usually mutated in the majority of acquired nevi, but hardly ever both at once. ...
Introduction:
Due to its aggressiveness, cutaneous melanoma (CM) is responsible for most skin cancer-related deaths worldwide. The origin of CM is closely linked to the appearance of UV-induced somatic mutations in melanocytes present in normal skin or in CM precursor lesions (nevi or dysplastic nevi). In recent years, new NGS studies performed on CM tissue have increased the understanding of the genetic somatic changes underlying melanomagenesis and CM tumor progression.
Methods:
We reviewed the literature using all important scientific databases. All articles related to genomic mutations in CM as well as normal skin and nevi were included, in particular those related to somatic mutations produced by UV radiation.
Conclusions:
CM development and progression are strongly associated with exposure to UV radiation, although each melanoma subtype has different characteristic genetic alterations and evolutionary trajectories. While BRAF and NRAS mutations are common in the early stages of tumor development for most CM subtypes, changes in CDKN2A, TP53 and PTEN, together with TERT promoter mutations, are especially common in advanced stages. Additionally, large genome duplications, loss of heterozygosity, and copy number variations are hallmarks of metastatic disease. Finally, the mutations driving melanoma targeted-therapy drug resistance are also summarized. The complete sequential stages of clonal evolution leading to CM onset from normal skin or nevi are still unknown, so further studies are needed in this field to shed light on the molecular pathways involved in CM malignant transformation and in melanoma acquired drug resistance.
... As far as the cell culture is concerned, the human melanoma cell line SK-MEL-28, routinely used in skin cancer research and able to form tumors in nude mice, was used as a skin cancer model and compared with the human immortalized keratinocyte cell line, HaCaT (American Type Culture Collection, ATCC), which was chosen as the control health skin model [21,22]. The cell lines were cultured in complete Dulbecco's modified Eagle's medium (DMEM; Hyclone, South Logan, UT, USA) with high glucose (4.5 g/L), supplemented with 10% fetal bovine serum (FBS, HyClone), 2 mM-glutamine, and 100 IU/mL penicillin/streptomycin (Invitrogen, Carlsbad, CA, USA). ...
We exploit Surface-Enhanced Raman Scattering (SERS) to investigate aqueous droplets of genomic DNA deposited onto silver-coated silicon nanowires, and we show that it is possible to efficiently discriminate between spectra of tumoral and healthy cells. To assess the robustness of the proposed technique, we develop two different statistical approaches, one based on the Principal Components Analysis of spectral data and one based on the computation of the ℓ2 distance between spectra. Both methods prove to be highly efficient, and we test their accuracy via the Cohen’s κ statistics. We show that the synergistic combination of the SERS spectroscopy and the statistical analysis methods leads to efficient and fast cancer diagnostic applications allowing rapid and unexpansive discrimination between healthy and tumoral genomic DNA alternative to the more complex and expensive DNA sequencing.
... them are point mutations of C ! T (7). The most common mutation, found in around 50% of all melanoma cases, is the BRAF gene mutation, most often the BRAF V600E where valine is substituted with a glutamic acid (35). Interestingly, the BRAF V600E mutation can also be found in over 80% of benign nevi (36,37) and is thought to be the driver mutation for the formation of acquired nevi (38). ...
... Interestingly, the BRAF V600E mutation can also be found in over 80% of benign nevi (36,37) and is thought to be the driver mutation for the formation of acquired nevi (38). Other common mutations found in melanoma are NRAS (neuroblastoma RAS viral oncogene homolog), c-Kit (35) and CDKN2A (cyclin dependent kinase inhibitor 2A) the latter of which associates with familial atypical multiple mole melanoma syndrome (FAMMM) (39). Pigmentation and melanocyte differentiation related mutations in MC1R (melanocortin 1 receptor) and MITF (microphthalmia associated transcription factor) have also been found in melanoma. ...
The incidence of cutaneous melanoma is rapidly increasing worldwide. Cutaneous melanoma is an aggressive type of skin cancer, which originates from malignant transformation of pigment producing melanocytes. The main risk factor for melanoma is ultraviolet (UV) radiation, and thus it often arises from highly sun-exposed skin areas and is characterized by a high mutational burden. In addition to melanoma-associated mutations such as BRAF, NRAS, PTEN and cell cycle regulators, the expansion of melanoma is affected by the extracellular matrix surrounding the tumor together with immune cells. In the early phases of the disease, hyaluronan is the major matrix component in cutaneous melanoma microenvironment. It is a high-molecular weight polysaccharide involved in several physiological and pathological processes. Hyaluronan is involved in the inflammatory reactions associated with UV radiation but its role in melanomagenesis is still unclear. Although abundant hyaluronan surrounds epidermal and dermal cells in normal skin and benign nevi, its content is further elevated in dysplastic lesions and local tumors. At this stage hyaluronan matrix may act as a protective barrier against melanoma progression, or alternatively against immune cell attack. While in advanced melanoma, the content of hyaluronan decreases due to altered synthesis and degradation, and this correlates with poor prognosis. This review focuses on hyaluronan matrix in cutaneous melanoma and how the changes in hyaluronan metabolism affect the progression of melanoma.
... chromosome deletions, which include PTEN, are also associated with melanoma metastasis [31]. Alterations in other important constituents of the PI3K/AKT pathway, namely RAC1, PIK3CA, AKT3, PREX2, and AKT1, are also known to occur in melanoma [1,5,8,32,33]. Phosphorylated AKT was discovered to have a significantly higher expression in CNS metastases [34]. ...
Simple Summary
Melanoma is a skin cancer with a high mortality and a dramatically rising presence worldwide. Recent research has shed new light on the genetic events that promote melanoma progression and confer metastatic potential. This review summarizes the role of molecular pathways, genomic factors, and the tumor microenvironment in the progression from local melanoma to distant disease. Further characterization of these elements is necessary to identify relevant prognostic factors and potential new therapeutic targets.
Abstract
Melanoma is a deadly skin cancer with rapidly increasing incidence worldwide. The discovery of the genetic drivers of melanomagenesis in the last decade has led the World Health Organization to reclassify melanoma subtypes by their molecular pathways rather than traditional clinical and histopathologic features. Despite this significant advance, the genomic and transcriptomic drivers of metastatic progression are less well characterized. This review describes the known molecular pathways of cutaneous and uveal melanoma progression, highlights recently identified pathways and mediators of metastasis, and touches on the influence of the tumor microenvironment on metastatic progression and treatment resistance. While targeted therapies and immune checkpoint blockade have significantly aided in the treatment of advanced disease, acquired drug resistance remains an unfortunately common problem, and there is still a great need to identify potential prognostic markers and novel therapeutic targets to aid in such cases.
... Melanoma is one of the most devastating types of cancer that occurs frequently, which depends on various environmental factors [1]. Abnormal genetic changes which are caused by environmental factors are responsible for malignant alteration in melanocytes [2]. Skin cancer is differentiated into melanoma and non-melanoma skin cancer occurring worldwide [3]. ...
Melanoma is known to aggressively metastasize and is one of the prominent causes of skin cancer mortality. This study was designed to assess the molecular mechanism of decursinol angelate (DA) against murine melanoma cell line (B16F10 cells). Treatment of DA resulted in growth inhibition and cell cycle arrest at G0/G1 (p < 0.001) phase, evaluated through immunoblotting. Moreover, autophagy-related proteins such as ATG-5 (p < 0.0001), ATG-7 (p < 0.0001), beclin-1 (p < 0.0001) and transition of LC3-I to LC3-II (p < 0.0001) were markedly decreased, indicating autophagosome inhibition. Additionally, DA treatment triggered apoptotic events which were corroborated by the occurrence of distorted nuclei, elevated reactive oxygen species (ROS) levels and reduction in the
mitochondrial membrane potential. Subsequently, there was an increase in the expression of proapoptotic
protein Bax in a dose-dependent manner, with the corresponding downregulation of Bcl-2
expression and cytochrome C expression following 24 h DA treatment in A375.SM and B16F10 cells. We substantiated our results for apoptotic occurrence through flow cytometry in B16F10 cells. Furthermore, we treated B16F10 cells with N-acetyl-L-cysteine (NAC). NAC treatment upregulated ATG-5 (p < 0.0001), beclin-1 (p < 0.0001) and LC3-I to LC3-II (p < 0.0001) conversion, which was inhibited in the DA treatment group. We also noticed a systematic upregulation of important markers for progression of G1 cell phase such as CDK-2 (p < 0.029), CDK-4 (p < 0.036), cyclin D1 (p < 0.0003)
and cyclin E (p < 0.020) upon NAC treatment. In addition, we also observed a significant fold reduction (p < 0.05) in ROS fluorescent intensity and the expression of Bax (p < 0.0001), cytochrome C (p < 0.0001), cleaved caspase-9 (p > 0.010) and cleaved caspase-3 (p < 0.0001). NAC treatment was able to ameliorate DA-induced apoptosis and cell cycle arrest to support our finding. Our in vivo xenograft model also revealed similar findings, such as downregulation of CDK-2 (p < 0.0001) and CDK-4 (p < 0.0142) and upregulation of Bax (p < 0.0001), cytochrome C (p < 0.0001), cleaved caspase
3 (p < 0.0001) and cleaved caspase 9 (p < 0.0001). In summary, our study revealed that DA is an effective treatment against B16F10 melanoma cells and xenograft mice model.
... α-tubulin was detected as a loading control. Experiments (n = 3) were performed in triplicate migratory and metastatic capacity (Testa, Castelli, & Pelosi, 2017). In addition, MAPK also promotes hyperactivation of the transcription factor NF-κB that regulates the expression of many antiapoptotic, proproliferative, and prometastatic genes (Liu et al., 2007). ...
Malignant melanoma is the deadliest skin cancer, due to its propensity to metastasize. MAPKs and NF‐κB pathways are constitutively activated in melanoma and promote cell proliferation, cell invasion, metastasis formation, and resistance to therapeutic regimens. Thus, they represent potential targets for melanoma prevention and treatment. Phytochemicals are gaining considerable attention for the management of melanoma because of their several cellular and molecular targets. A screening of a small library of sesquiterpenes lactones selected cynaropicrin, isolated from the aerial parts of Centaurea drabifolia subsp. detonsa, for its potential anticancer effect against melanoma cells. Treatment of human melanoma cells A375 with cynaropicrin resulted in inhibition of cell proliferation and induction of caspase‐3‐dependent apoptosis. Furthermore, cynaropicrin reduced several cellular malignant features such migration, invasion, and colonies formation through the inhibition of ERK1/2 and NF‐κB activity. Cynaropicrin was able to reduce intracellular reactive oxygen species generation, which are involved in all the stages of carcinogenesis. Indeed, cynaropicrin increased the expression of several antioxidant genes, such as glutamate–cysteine ligase and heme oxygenase‐1, by promoting the activation of the transcription factor Nrf‐2. In conclusion, our results individuate cynaropicrin as a potential adjuvant chemotherapeutic agent for melanoma by targeting several protumorigenic signaling pathways.
... In approximately 50% of all melanomas, a mutation in the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) has been found (2). This results in the constitutive activation of BRAF, resulting in the overactivation of the MAPK growth pathway and melanoma proliferation. ...
Purpose:
The extracellular matrix (ECM) is an intriguing yet understudied component of therapy resistance. Here we investigated the role of ECM remodeling by the collagenase MT1-MMP in conferring resistance of BRAF-mutant melanoma to BRAF inhibitor therapy.
Experimental design:
Publicly available RNA sequencing (RNAseq) data and reverse-phase-protein-array (RPPA) were used to determine the relevance of MT1-MMP up-regulation in BRAFi-resistant melanoma in patients, PDX and cell line derived tumors. shRNA-mediated knockdown of MT1-MMP; inhibition via the selective MT1-MMP/MMP2 inhibitor, ND322; or overexpression of MT1-MMP were used to assess the role of MT1-MMP in mediating resistance to BRAFi.
Results:
MT1-MMP was consistently up-regulated in post-treatment tumor samples derived from patients upon disease progression and melanoma xenografts and cell lines that acquired resistance to BRAFi. shRNA or ND322 mediated inhibition of MT1-MMP synergized with BRAFi leading to re-sensitization of resistant cells and tumors to BRAFi. Resistance depends on the ability of cells to cleave the ECM. Resistant cells seeded in MT1-MMP un-cleavable matrixes were re-sensitized to BRAFi similarly to MT1-MMP inhibition. This is due to the inability of cells to activate integrinß1/FAK signaling, as restoration of integrinß1 activity is sufficient to maintain resistance to BRAFi in the context of MT1-MMP inhibition. Finally, the increase in MT1-MMP in BRAFi-resistant cells is TGFß-dependent, as inhibition of TGFb receptors I/II dampens MT1-MMP overexpression and restores sensitivity to BRAF inhibition.
Conclusions:
BRAF inhibition results in a selective pressure towards higher expression of MT1-MMP. MT1-MMP is pivotal to an ECM-based signaling pathway that confers resistance to BRAFi therapy.
... Molecular studies have revolutionized melanoma therapy, particularly with the discovery of several molecular biomarkers that are expressed selectively in certain subgroups of patients and are suitable for target therapy [117]. On the basis of the pattern of the most recurrent gene mutations, four subtypes were identified: mutant BRAF, mutant RAS, mutant NF1, and triple-wildtype (kit mutations, focal amplifications, and complex structural rearrangements are the typical characteristics of the triple-WT subtype) [118]. ...
