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• W2970347002 abstract "Melanoma is the leading cause of death due to cutaneous malignancy and its incidence is on the rise. Several signaling pathways, including receptor tyrosine kinases, have been recognized to have an etiopathogenetic role in the development and progression of precursor melanocytic lesions and malignant melanoma. Among those, the hepatocyte growth factor/MET (HGF/MET) axis is emerging as a critical player not only in the tumor itself but also in the immune microenvironment in which the tumor grows and advances in its development. Moreover, the activation of this pathway has emerged as a paradigm of tumor resistance to modern targeted therapies, and the assessment of its expression in patients' samples may be a valuable biomarker of tumor progression and response to targeted therapy. Here we summarize our current understanding of this important receptor tyrosine kinase in normal melanocyte proliferation/motility, in tumor progression and metastasis, its genetic alterations in certain subtype of melanocytic lesions, and how its pathway has been explored for the development of selective inhibitors. Melanoma is the leading cause of death due to cutaneous malignancy and its incidence is on the rise. Several signaling pathways, including receptor tyrosine kinases, have been recognized to have an etiopathogenetic role in the development and progression of precursor melanocytic lesions and malignant melanoma. Among those, the hepatocyte growth factor/MET (HGF/MET) axis is emerging as a critical player not only in the tumor itself but also in the immune microenvironment in which the tumor grows and advances in its development. Moreover, the activation of this pathway has emerged as a paradigm of tumor resistance to modern targeted therapies, and the assessment of its expression in patients' samples may be a valuable biomarker of tumor progression and response to targeted therapy. Here we summarize our current understanding of this important receptor tyrosine kinase in normal melanocyte proliferation/motility, in tumor progression and metastasis, its genetic alterations in certain subtype of melanocytic lesions, and how its pathway has been explored for the development of selective inhibitors. Melanoma is the most common lethal cancer among all skin malignancies, with a high propensity for metastasis.1Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2018.CA Cancer J Clin. 2018; 68: 7-30Crossref PubMed Scopus (6444) Google Scholar The 5-year survival rate drops from about 98% in patients with early, localized disease to only 20% in those with metastatic melanoma.1Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2018.CA Cancer J Clin. 2018; 68: 7-30Crossref PubMed Scopus (6444) Google Scholar The estimated 5-year overall survival is 34% even in the era of immunotherapy such as the PD-1 inhibitor pembrolizumab. The annual incidence of malignant melanoma has increased by approximately 50% over the last decade.1Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2018.CA Cancer J Clin. 2018; 68: 7-30Crossref PubMed Scopus (6444) Google Scholar, 2Jemal A. Siegel R. Ward E. Murray T. Xu J. Smigal C. Thun M.J. Cancer statistics, 2006.CA Cancer J Clin. 2006; 56: 106-130Crossref PubMed Scopus (5508) Google Scholar A variety of pathogenic mutations are associated with the initiation, progression, and metastasis of melanoma. Of these, the BRAFV600E mutation has been found in approximately half of malignant melanomas and tend to be more frequent in low–cumulative sun-induced damage melanomas.3Davies H. Bignell G.R. Cox C. Stephens P. Edkins S. Clegg S. et al.Mutations of the BRAF gene in human cancer.Nature. 2002; 417: 949-954Crossref PubMed Scopus (8271) Google Scholar, 4Elder D. Lazar A. Barnhill B. Massi D. Bastian B. Mihm M.J. Cook M. Nagore E. de la Fouchardiere A. Scolyer R. Gerami P. Yun S. Melanocytic tumours: introduction.in: Elder D. Massi D. Scolyer R. Willemze R. WHO Classification of Skin Tumours. ed 4. 2018: 66-75Google Scholar On the other hand, NRAS, NF1, and other BRAF mutations are more frequently present in high–chronic sun-induced damage melanomas.4Elder D. Lazar A. Barnhill B. Massi D. Bastian B. Mihm M.J. Cook M. Nagore E. de la Fouchardiere A. Scolyer R. Gerami P. Yun S. Melanocytic tumours: introduction.in: Elder D. Massi D. Scolyer R. Willemze R. WHO Classification of Skin Tumours. ed 4. 2018: 66-75Google Scholar, 5Shain A.H. Bastian B.C. From melanocytes to melanomas.Nat Rev Cancer. 2016; 16: 345-358Crossref PubMed Scopus (447) Google Scholar Therapies targeting these mutations and relevant pathways have led to improved patient survival. However, the treatment of locally advanced or metastatic melanomas often requires systemic or combination approaches, including immunotherapy (the checkpoint inhibitors anti–programmed cell death protein 1, anti– programmed cell death protein ligand 1, or cytotoxic T lymphocyte–associated antigen 4 antibodies), targeted therapy [BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors], and chemotherapy.6Chapman P.B. Hauschild A. Robert C. Haanen J.B. Ascierto P. Larkin J. Dummer R. Garbe C. Testori A. Maio M. Hogg D. Lorigan P. Lebbe C. Jouary T. Schadendorf D. Ribas A. O'Day S.J. Sosman J.A. Kirkwood J.M. Eggermont A.M. Dreno B. Nolop K. Li J. Nelson B. Hou J. Lee R.J. Flaherty K.T. McArthur G.A. Group B.-S. Improved survival with vemurafenib in melanoma with BRAF V600E mutation.N Engl J Med. 2011; 364: 2507-2516Crossref PubMed Scopus (6115) Google Scholar, 7Wolchok J.D. Chiarion-Sileni V. Gonzalez R. Rutkowski P. Grob J.J. Cowey C.L. Lao C.D. Wagstaff J. Schadendorf D. Ferrucci P.F. Smylie M. Dummer R. Hill A. Hogg D. Haanen J. Carlino M.S. Bechter O. Maio M. Marquez-Rodas I. Guidoboni M. McArthur G. Lebbe C. Ascierto P.A. Long G.V. Cebon J. Sosman J. Postow M.A. Callahan M.K. Walker D. Rollin L. Bhore R. Hodi F.S. Larkin J. Overall survival with combined nivolumab and ipilimumab in advanced melanoma.N Engl J Med. 2017; 377: 1345-1356Crossref PubMed Scopus (2212) Google Scholar The absolute survival rate remains quite low.8Hamid O. Robert C. Daud A. Hodi F.S. Hwu W.J. Kefford R. Wolchok J.D. Hersey P. Joseph R. Weber J.S. Dronca R. Mitchell T.C. Patnaik A. Zarour H.M. Joshua A.M. Zhao Q. Jensen E. Ahsan S. Ibrahim N. Ribas A. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.Ann Oncol. 2019; 30: 582-588Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar Furthermore, immunotherapy and targeted therapy are often limited by high rates of resistance.9Hugo W. Zaretsky J.M. Sun L. Song C. Moreno B.H. Hu-Lieskovan S. Berent-Maoz B. Pang J. Chmielowski B. Cherry G. Seja E. Lomeli S. Kong X. Kelley M.C. Sosman J.A. Johnson D.B. Ribas A. Lo R.S. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma.Cell. 2016; 165: 35-44Abstract Full Text Full Text PDF PubMed Scopus (1737) Google Scholar, 10Caenepeel S. Cooke K. Wadsworth S. Huang G. Robert L. Moreno B.H. Parisi G. Cajulis E. Kendall R. Beltran P. Ribas A. Coxon A. Hughes P.E. MAPK pathway inhibition induces MET and GAB1 levels, priming BRAF mutant melanoma for rescue by hepatocyte growth factor.Oncotarget. 2017; 8: 17795-17809Crossref PubMed Scopus (29) Google Scholar Therefore, a better understanding of the molecular events involved in the progression and therapeutic resistance of melanoma is necessary. Increasing attention has been drawn to the critical role of the hepatocyte growth factor (HGF)/MET pathway in melanoma development, progression, and therapeutic resistance.10Caenepeel S. Cooke K. Wadsworth S. Huang G. Robert L. Moreno B.H. Parisi G. Cajulis E. Kendall R. Beltran P. Ribas A. Coxon A. Hughes P.E. MAPK pathway inhibition induces MET and GAB1 levels, priming BRAF mutant melanoma for rescue by hepatocyte growth factor.Oncotarget. 2017; 8: 17795-17809Crossref PubMed Scopus (29) Google Scholar, 11Al-U'datt D.G. Al-Husein B.A.A. Qasaimeh G.R. A mini-review of c-Met as a potential therapeutic target in melanoma.Biomed Pharmacother. 2017; 88: 194-202Crossref PubMed Scopus (25) Google Scholar MET receptor, also known as HGF receptor , is expressed in the epithelial cells of many tissues, including skin, and the tumorigenic effect of the HGF/MET pathway has long been observed in malignancies of various organs. Therapies targeted toward this pathway have yielded improved clinical outcomes, especially in renal cell and lung carcinomas.12De Silva D.M. Roy A. Kato T. Cecchi F. Lee Y.H. Matsumoto K. Bottaro D.P. Targeting the hepatocyte growth factor/Met pathway in cancer.Biochem Soc Trans. 2017; 45: 855-870Crossref PubMed Scopus (42) Google Scholar, 13Schöffski P. Wozniak A. Escudier B. Rutkowski P. Anthoney A. Bauer S. Sufliarsky J. van Herpen C. Lindner L.H. Grünwald V. Zakotnik B. Lerut E. Debiec-Rychter M. Marréaud S. Lia M. Raveloarivahy T. Collette S. Albiges L. Crizotinib achieves long-lasting disease control in advanced papillary renal-cell carcinoma type 1 patients with MET mutations or amplification. EORTC 90101 CREATE trial.Eur J Cancer. 2017; 87: 147-163Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Therefore, the observation of MET activation in melanoma may open up a new possibility of aid in melanoma treatment. MET signaling aberrations have been found in melanomas at both sun-exposed and sun-shielded sites. Commonly found MET alterations include MET amplifications in desmoplastic melanoma, a high–chronic sun-induced damage melanoma, and MET rearrangements in Spitz melanoma as well as in its benign/intermediate precursor lesions.4Elder D. Lazar A. Barnhill B. Massi D. Bastian B. Mihm M.J. Cook M. Nagore E. de la Fouchardiere A. Scolyer R. Gerami P. Yun S. Melanocytic tumours: introduction.in: Elder D. Massi D. Scolyer R. Willemze R. WHO Classification of Skin Tumours. ed 4. 2018: 66-75Google Scholar In the most recent large-scale whole-genome sequencing analysis of melanoma, which included 183 patient samples of cutaneous, mucosal, and acral subtypes, frequent MET aberrations were demonstrated, with 24% gene amplifications, 9% single-nucleotide variations/deletions, and 1% structural variants.14Hayward N.K. Wilmott J.S. Waddell N. Johansson P.A. Field M.A. Nones K. et al.Whole-genome landscapes of major melanoma subtypes.Nature. 2017; 545: 175-180Crossref PubMed Scopus (728) Google Scholar Therapies targeting the HGF/MET pathway have shown promising results in inhibiting melanoma growth and metastasis in preclinical studies. However, translations of MET inhibitors into clinical studies as single-therapy agents in melanoma, as in other cancers, have been largely unfruitful, possibly due to the complex crosstalk of the HGF/MET pathway with other oncogenic pathways. Recent ongoing efforts include the investigation of synergistic therapeutic effects of combination therapies involving MET inhibitors, and mechanistic studies of MET targeting to overcome therapeutic resistance. These studies promise to better define the roles of this pathway in melanoma and other malignancies and to more precisely guide clinical applications of its targeted therapy. The proto-oncogene MET on the 7q31 locus encodes MET, alias HGF receptor.15Bottaro D.P. Rubin J.S. Faletto D.L. Chan A.M. Kmiecik T.E. Vande Woude G.F. Aaronson S.A. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product.Science. 1991; 251: 802-804Crossref PubMed Scopus (2081) Google Scholar HGF, a pleiotropic heparin-binding protein, binds to MET and elicits multiple biological activities such as mitogenic, motogenic, and morphogenic responses in various cell types, including melanocytes.16Birchmeier C. Birchmeier W. Gherardi E. Vande Woude G.F. Met, metastasis, motility and more.Nat Rev Mol Cell Biol. 2003; 4: 915-925Crossref PubMed Scopus (2225) Google Scholar HGF is produced as an inactive single-chain precursor that is processed to yield an active heterodimer of one α and one β chain linked by a disulfide bond.17Nakamura T. Nishizawa T. Hagiya M. Seki T. Shimonishi M. Sugimura A. Tashiro K. Shimizu S. Molecular cloning and expression of human hepatocyte growth factor.Nature. 1989; 342: 440-443Crossref PubMed Scopus (1978) Google Scholar MET is a transmembrane receptor composed of a glycosylated, extracellular α subunit and a transmembrane β subunit.18Rodrigues G.A. Naujokas M.A. Park M. Alternative splicing generates isoforms of the met receptor tyrosine kinase which undergo differential processing.Mol Cell Biol. 1991; 11: 2962-2970Crossref PubMed Scopus (121) Google Scholar The α and the first 212 residues of the β subunit serve as the extracellular binding site for HGF.19Gherardi E. Youles M.E. Miguel R.N. Blundell T.L. Iamele L. Gough J. Bandyopadhyay A. Hartmann G. Butler P.J. Functional map and domain structure of MET, the product of the c-met protooncogene and receptor for hepatocyte growth factor/scatter factor.Proc Natl Acad Sci U S A. 2003; 100: 12039-12044Crossref PubMed Scopus (149) Google Scholar The intracellular portion of the β subunit contains three major domains: the juxtamembrane domain, the kinase domain, and the C-terminal docking site.16Birchmeier C. Birchmeier W. Gherardi E. Vande Woude G.F. Met, metastasis, motility and more.Nat Rev Mol Cell Biol. 2003; 4: 915-925Crossref PubMed Scopus (2225) Google Scholar Upon ligand binding, two tyrosine residues in the kinase domain, Y1234 and Y1235, are phosphorylated. Phosphorylation of two critical tyrosine residues, Y1349 and Y1356, within the C-terminal docking site recruits multiple intracellular molecules, including GRB2–associated-binding protein 1 (GAB1), growth factor receptor–bound protein 2 (GRB2), phosphatidylinositol 3 kinase (PI3K), phospholipase C γ, Src, and Shc, via binding to a Src homology 2 domain or other recognition motifs.11Al-U'datt D.G. Al-Husein B.A.A. Qasaimeh G.R. A mini-review of c-Met as a potential therapeutic target in melanoma.Biomed Pharmacother. 2017; 88: 194-202Crossref PubMed Scopus (25) Google Scholar, 16Birchmeier C. Birchmeier W. Gherardi E. Vande Woude G.F. Met, metastasis, motility and more.Nat Rev Mol Cell Biol. 2003; 4: 915-925Crossref PubMed Scopus (2225) Google Scholar Consequently, multiple signaling pathways controlling cell survival, cell cycle progression, motility, and migration, including the PI3K/Akt, Ras/mitogen-activated protein kinase (MAPK), Rac1/cell division control protein 42 pathways, are activated (Figure 1).16Birchmeier C. Birchmeier W. Gherardi E. Vande Woude G.F. Met, metastasis, motility and more.Nat Rev Mol Cell Biol. 2003; 4: 915-925Crossref PubMed Scopus (2225) Google Scholar Under normal physiologic conditions, HGF produced by cells of mesenchymal origin acts in a paracrine manner to stimulate MET during embryonic development and throughout adulthood.16Birchmeier C. Birchmeier W. Gherardi E. Vande Woude G.F. Met, metastasis, motility and more.Nat Rev Mol Cell Biol. 2003; 4: 915-925Crossref PubMed Scopus (2225) Google Scholar Normal human melanocytes do not secrete HGF but are receptive to HGF through the expression of MET.20Saitoh K. Takahashi H. Sawada N. Parsons P.G. Detection of the c-met proto-oncogene product in normal skin and tumours of melanocytic origin.J Pathol. 1994; 174: 191-199Crossref PubMed Scopus (46) Google Scholar HGF functions as a mitogen, stimulating melanocyte proliferation, in synergy with basic fibroblast growth factor and mast cell growth factor.21Halaban R. Rubin J.S. Funasaka Y. Cobb M. Boulton T. Faletto D. Rosen E. Chan A. Yoko K. White W. Met and hepatocyte growth factor/scatter factor signal transduction in normal melanocytes and melanoma cells.Oncogene. 1992; 7: 2195-2206PubMed Google Scholar HGF/MET signaling also promotes melanocyte motility and maintains high levels of tyrosinase activity and melanin content.20Saitoh K. Takahashi H. Sawada N. Parsons P.G. Detection of the c-met proto-oncogene product in normal skin and tumours of melanocytic origin.J Pathol. 1994; 174: 191-199Crossref PubMed Scopus (46) Google Scholar, 21Halaban R. Rubin J.S. Funasaka Y. Cobb M. Boulton T. Faletto D. Rosen E. Chan A. Yoko K. White W. Met and hepatocyte growth factor/scatter factor signal transduction in normal melanocytes and melanoma cells.Oncogene. 1992; 7: 2195-2206PubMed Google Scholar Ubiquitous overexpression of HGF in transgenic mice leads to hyperpigmentation in neonatal and adult skin and hyperproliferation of melanocytes in ectopic tissues.22Takayama H. La Rochelle W.J. Anver M. Bockman D.E. Merlino G. Scatter factor/hepatocyte growth factor as a regulator of skeletal muscle and neural crest development.Proc Natl Acad Sci U S A. 1996; 93: 5866-5871Crossref PubMed Scopus (178) Google Scholar In addition, the up-regulation of MET expression via melanocyte-inducing transcription factor has been found to protect melanocytes from apoptosis.23Beuret L. Flori E. Denoyelle C. Bille K. Busca R. Picardo M. Bertolotto C. Ballotti R. Up-regulation of MET expression by alpha-melanocyte-stimulating hormone and MITF allows hepatocyte growth factor to protect melanocytes and melanoma cells from apoptosis.J Biol Chem. 2007; 282: 14140-14147Crossref PubMed Scopus (67) Google Scholar Under certain insults such as UV radiation, melanocyte-inducing transcription factor could directly bind to the MET promoter in response to the increased level of α-melanocyte–stimulating hormone,23Beuret L. Flori E. Denoyelle C. Bille K. Busca R. Picardo M. Bertolotto C. Ballotti R. Up-regulation of MET expression by alpha-melanocyte-stimulating hormone and MITF allows hepatocyte growth factor to protect melanocytes and melanoma cells from apoptosis.J Biol Chem. 2007; 282: 14140-14147Crossref PubMed Scopus (67) Google Scholar further emphasizing the complexity of the interplay of different pathways. Other studies have also revealed the regulatory roles of HGF/MET signaling in the development of melanocytes from neural crest.24Kos L. Aronzon A. Takayama H. Maina F. Ponzetto C. Merlino G. Pavan W. Hepatocyte growth factor/scatter factor-MET signaling in neural crest-derived melanocyte development.Pigment Cell Res. 1999; 12: 13-21Crossref PubMed Scopus (73) Google Scholar HGF promotes melanoblast survival and differentiation into pigmented melanocytes in vitro. Both in vitro and in vivo studies in mouse transgenic embryos have shown that the HGF/MET signaling can influence the initial development of neural crest–derived melanocytes.24Kos L. Aronzon A. Takayama H. Maina F. Ponzetto C. Merlino G. Pavan W. Hepatocyte growth factor/scatter factor-MET signaling in neural crest-derived melanocyte development.Pigment Cell Res. 1999; 12: 13-21Crossref PubMed Scopus (73) Google Scholar These studies not only offer a window on the role of this signaling pathway on physiologic melanocyte functions, but also highlight our incomplete understating and the need for additional studies. In malignancies, the HGF/MET pathway is aberrantly activated through several mechanisms, including paracrine signaling, activating mutations, overexpression, or autocrine loop formation.25Lai A.Z. Abella J.V. Park M. Crosstalk in Met receptor oncogenesis.Trends Cell Biol. 2009; 19: 542-551Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar Abnormalities in receptor tyrosine kinase (RTK) expression have been demonstrated to contribute to melanoma development and progression.26Easty D.J. Gray S.G. O'Byrne K.J. O'Donnell D. Bennett D.C. Receptor tyrosine kinases and their activation in melanoma.Pigment Cell Melanoma Res. 2011; 24: 446-461Crossref PubMed Scopus (62) Google Scholar In transgenic mice, Ret overexpression or MET activation could lead to melanoma development.27Otsuka T. Takayama H. Sharp R. Celli G. LaRochelle W.J. Bottaro D.P. Ellmore N. Vieira W. Owens J.W. Anver M. Merlino G. c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype.Cancer Res. 1998; 58: 5157-5167PubMed Google Scholar With advancement in technologies such as whole-genome sequencing, multiple forms of RTK aberrations have been discovered in melanoma cell lines and patient-derived samples.1Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2018.CA Cancer J Clin. 2018; 68: 7-30Crossref PubMed Scopus (6444) Google Scholar, 14Hayward N.K. Wilmott J.S. Waddell N. Johansson P.A. Field M.A. Nones K. et al.Whole-genome landscapes of major melanoma subtypes.Nature. 2017; 545: 175-180Crossref PubMed Scopus (728) Google Scholar More than 20 RTK families, including epidermal growth factor receptor, extracellular region binding proteins 2 and 4, Kit, fibroblast growth factor receptor, MET, and platelet-derived growth factor receptor, are involved in melanoma tumorigenesis.14Hayward N.K. Wilmott J.S. Waddell N. Johansson P.A. Field M.A. Nones K. et al.Whole-genome landscapes of major melanoma subtypes.Nature. 2017; 545: 175-180Crossref PubMed Scopus (728) Google Scholar RTK alterations are frequently identified in cutaneous, acral, and mucosal melanomas, and may represent promising therapeutic targets. In a subset of melanocytic neoplasms, recurrent rearrangements of kinases, have been described as a mechanism of oncogenic activation.28Wiesner T. He J. Yelensky R. Esteve-Puig R. Botton T. Yeh I. Lipson D. Otto G. Brennan K. Murali R. Garrido M. Miller V.A. Ross J.S. Berger M.F. Sparatta A. Palmedo G. Cerroni L. Busam K.J. Kutzner H. Cronin M.T. Stephens P.J. Bastian B.C. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas.Nat Commun. 2014; 5: 3116Crossref PubMed Scopus (405) Google Scholar, 29Tetzlaff M.T. Reuben A. Billings S.D. Prieto V.G. Curry J.L. Toward a molecular-genetic classification of spitzoid neoplasms.Clin Lab Med. 2017; 37: 431-448Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar The resulting chimeric proteins are constitutively active, stimulating oncogenic signaling pathways. In particular, gene rearrangements of MET resulting in in-frame MET kinase fusions are found in Spitz tumors and Spitzoid melanomas.30Yeh I. Botton T. Talevich E. Shain A.H. Sparatta A.J. de la Fouchardiere A. Mully T.W. North J.P. Garrido M.C. Gagnon A. Vemula S.S. McCalmont T.H. LeBoit P.E. Bastian B.C. Activating MET kinase rearrangements in melanoma and Spitz tumours.Nat Commun. 2015; 6: 7174Crossref PubMed Scopus (105) Google Scholar MET fusions tend to occur in younger patients (with an average age of onset of 20 years), and are present across benign, atypical, to malignant lesions, suggesting early occurrence of the MET fusions during tumor progression.30Yeh I. Botton T. Talevich E. Shain A.H. Sparatta A.J. de la Fouchardiere A. Mully T.W. North J.P. Garrido M.C. Gagnon A. Vemula S.S. McCalmont T.H. LeBoit P.E. Bastian B.C. Activating MET kinase rearrangements in melanoma and Spitz tumours.Nat Commun. 2015; 6: 7174Crossref PubMed Scopus (105) Google Scholar Common mutations in melanomas involving NRAS, NF1, or BRAF are usually not present in Spitzoid neoplasms. However, some of them can become aggressive and metastasize. These lesions may require systemic therapy, but targeted therapeutic options for these melanocytic lesions do not currently exist. Since MET fusions occur in a subset of Spitzoid melanomas in a mutually exclusive pattern with activating mutations in known melanoma oncogenes, they may represent a unique therapeutic target in those lesions.29Tetzlaff M.T. Reuben A. Billings S.D. Prieto V.G. Curry J.L. Toward a molecular-genetic classification of spitzoid neoplasms.Clin Lab Med. 2017; 37: 431-448Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 30Yeh I. Botton T. Talevich E. Shain A.H. Sparatta A.J. de la Fouchardiere A. Mully T.W. North J.P. Garrido M.C. Gagnon A. Vemula S.S. McCalmont T.H. LeBoit P.E. Bastian B.C. Activating MET kinase rearrangements in melanoma and Spitz tumours.Nat Commun. 2015; 6: 7174Crossref PubMed Scopus (105) Google Scholar Additional functional studies in mouse models and larger cohorts of patients with specific mutations or other genetic alterations will be required to evaluate the effects of each of these genetic alterations in melanoma, and to further develop tailored therapeutic strategies. Multiple mechanisms that confer oncogenic potential to HGF and MET in a wide variety of human cancers have been described, including autocrine or paracrine loop formation, MET-activating mutations, structural variants, and gene amplification.25Lai A.Z. Abella J.V. Park M. Crosstalk in Met receptor oncogenesis.Trends Cell Biol. 2009; 19: 542-551Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar For example, a study showed that the HGF/MET autocrine loop stimulated the aberrant growth of melanocytes with endogenous MET overexpression and drove tumorigenesis in a transgenic mouse model.31Puri N. Ahmed S. Janamanchi V. Tretiakova M. Zumba O. Krausz T. Jagadeeswaran R. Salgia R. c-Met is a potentially new therapeutic target for treatment of human melanoma.Clin Cancer Res. 2007; 13: 2246-2253Crossref PubMed Scopus (136) Google Scholar Several other studies have also shown that some melanomas in humans can express both MET and HGF, in contrast to normal melanocytes, which rarely produce HGF, further confirming the formation of an autocrine loop in melanoma development.5Shain A.H. Bastian B.C. From melanocytes to melanomas.Nat Rev Cancer. 2016; 16: 345-358Crossref PubMed Scopus (447) Google Scholar, 32Shain A.H. Yeh I. Kovalyshyn I. Sriharan A. Talevich E. Gagnon A. Dummer R. North J. Pincus L. Ruben B. Rickaby W. D'Arrigo C. Robson A. Bastian B.C. The genetic evolution of melanoma from precursor lesions.N Engl J Med. 2015; 373: 1926-1936Crossref PubMed Scopus (622) Google Scholar, 33Li G. Schaider H. Satyamoorthy K. Hanakawa Y. Hashimoto K. Herlyn M. Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development.Oncogene. 2001; 20: 8125-8135Crossref PubMed Scopus (166) Google Scholar, 34Natali P.G. Nicotra M.R. Di Renzo M.F. Prat M. Bigotti A. Cavaliere R. Comoglio P.M. Expression of the c-Met/HGF receptor in human melanocytic neoplasms: demonstration of the relationship to malignant melanoma tumour progression.Br J Cancer. 1993; 68: 746-750Crossref PubMed Scopus (175) Google Scholar Various MET mutations have been identified in melanoma.35Zenali M. deKay J. Liu Z. Hamilton S. Zuo Z. Lu X. Bakkar R. Mills G. Broaddus R. Retrospective review of MET gene mutations.Oncoscience. 2015; 2: 533-541Crossref PubMed Scopus (28) Google Scholar Among these, activating mutations in the MET kinase domain are most closely associated with its oncogenic capacity.25Lai A.Z. Abella J.V. Park M. Crosstalk in Met receptor oncogenesis.Trends Cell Biol. 2009; 19: 542-551Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 36Schmidt L. Duh F.M. Chen F. Kishida T. Glenn G. Choyke P. Scherer S.W. Zhuang Z. Lubensky I. Dean M. Allikmets R. Chidambaram A. Bergerheim U.R. Feltis J.T. Casadevall C. Zamarron A. Bernues M. Richard S. Lips C.J. Walther M.M. Tsui L.C. Geil L. Orcutt M.L. Stackhouse T. Lipan J. Slife L. Brauch H. Decker J. Niehans G. Hughson M.D. Moch H. Storkel S. Lerman M.I. Linehan W.M. Zbar B. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas.Nat Genet. 1997; 16: 68-73Crossref PubMed Scopus (1314) Google Scholar, 37Athauda G. 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Overall survival with combined nivolumab and ipilimumab in advanced melanoma.N Engl J Med. 2017; 377: 1345-1356Crossref PubMed Scopus (2212) Google Scholar, 9Hugo W. Zaretsky J.M. Sun L. Song C. Moreno B.H. Hu-Lieskovan S. Berent-Maoz B. Pang J. Chmielowski B. Cherry G. Seja E. Lomeli S. Kong X. Kelley M.C. Sosman J.A. Johnson D.B. Ribas A. Lo R.S. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma.Cell. 2016; 165: 35-44Abstract Full Text Full Text PDF PubMed Scopus (1737) Google Scholar, 38Ma P.C. Tretiakova M.S. MacKinnon A.C. Ramnath N. Johnson C. Dietrich S. Seiwert T. Christensen J.G. Jagadeeswaran R. Krausz T. Vokes E.E. Husain A.N. Salgia R. 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• W2970347002 title "The Role of MET in Melanoma and Melanocytic Lesions" @default.
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