Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence

Oncogene volume 40, pages 4625–4651 (2021)Cite this article

Subjects

Abstract

This review provides a comprehensive landscape of HGF/c-MET (hepatocyte growth factor (HGF) /mesenchymal–epithelial transition factor (c-MET)) signaling pathway in cancers. First, we generalize the compelling influence of HGF/c-MET pathway on multiple cellular processes. Then, we present the genomic characterization of HGF/c-MET pathway in carcinogenesis. Furthermore, we extensively illustrate the malignant biological behaviors of HGF/c-MET pathway in cancers, in which hyperactive HGF/c-MET signaling is considered as a hallmark. In addition, we investigate the current clinical trials of HGF/c-MET-targeted therapy in cancers. We find that although HGF/c-MET-targeted therapy has led to breakthroughs in certain cancers, monotherapy of targeting HGF/c-MET has failed to demonstrate significant clinical efficacy in most cancers. With the advantage of the combinations of HGF/c-MET-targeted therapy, the exploration of more options of combinational targeted therapy in cancers may be the major challenge in the future.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Timeline of the terms used and hallmarks in HGF/c-MET pathway research.
Fig. 2: The illustration of the molecule mechanism of HGF/c-MET downstream signaling pathways and the crosstalk between c-MET and other cell signal transduction pathways.

Similar content being viewed by others

References

  1. Nakamura T, Nawa K, Ichihara A. Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochem Biophys Res Commun. 1984;122:1450–9.

    Article  CAS  PubMed  Google Scholar 

  2. Thaler FJ, Michalopoulos GK. Hepatopoietin A: partial characterization and trypsin activation of a hepatocyte growth factor. Cancer Res. 1985;45:2545–9.

    CAS  PubMed  Google Scholar 

  3. Zarnegar R, Michalopoulos G. Purification and biological characterization of human hepatopoietin A, a polypeptide growth factor for hepatocytes. Cancer Res. 1989;49:3314–20.

    CAS  PubMed  Google Scholar 

  4. Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, et al. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989;342:440–3.

    Article  CAS  PubMed  Google Scholar 

  5. Laguda B, Selden C, Jones M, Hodgson H, Spurr NK. Assignment of the hepatocyte growth factor (HGF) to chromosome 7q22-qter. Ann Hum Genet. 1991;55:213–6.

    Article  CAS  PubMed  Google Scholar 

  6. Stoker M, Gherardi E, Perryman M, Gray J. Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature. 1987;327:239–42.

    Article  CAS  PubMed  Google Scholar 

  7. Gherardi E, Sharpe M, Lane K, Sirulnik A, Stoker M. Hepatocyte growth factor/scatter factor (HGF/SF), the c-Met receptor and the behaviour of epithelial cells. Symp Soc Exp Biol. 1993;47:163–81.

    CAS  PubMed  Google Scholar 

  8. Weidner KM, Behrens J, Vandekerckhove J, Birchmeier W. Scatter factor: molecular characteristics and effect on the invasiveness of epithelial cells. J Cell Biol. 1990;111:2097–108.

    Article  CAS  PubMed  Google Scholar 

  9. Gille J, Khalik M, König V, Kaufmann R. Hepatocyte growth factor/scatter factor (HGF/SF) induces vascular permeability factor (VPF/VEGF) expression by cultured keratinocytes. J Invest Dermatol. 1998;111:1160–5.

    Article  CAS  PubMed  Google Scholar 

  10. Higashio K, Shima N, Goto M, Itagaki Y, Nagao M, Yasuda H, et al. Identity of a tumor cytotoxic factor from human fibroblasts and hepatocyte growth factor. Biochem Biophys Res Commun. 1990;170:397–404.

    Article  CAS  PubMed  Google Scholar 

  11. Rubin JS, Chan AM, Bottaro DP, Burgess WH, Taylor WG, Cech AC, et al. A broad-spectrum human lung fibroblast-derived mitogen is a variant of hepatocyte growth factor. Proc Natl Acad Sci USA. 1991;88:415–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schultz JM, Khan SN, Ahmed ZM, Riazuddin S, Waryah AM, Chhatre D, et al. Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39. Am J Hum Genet. 2009;85:25–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Morell RJ, Olszewski R, Tona R, Leitess S, Wafa TT, Taukulis I, et al. Noncoding microdeletion in mouse Hgf disrupts neural crest migration into the stria vascularis, reduces the endocochlear potential and suggests the neuropathology for human nonsyndromic deafness DFNB39. J Neurosci. 2020;40:2976–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cooper CS, Park M, Blair DG, Tainsky MA, Huebner K, Croce CM, et al. Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature. 1984;311:29–33.

    Article  CAS  PubMed  Google Scholar 

  15. Dean M, Park M, Le Beau MM, Robins TS, Diaz MO, Rowley JD, et al. The human met oncogene is related to the tyrosine kinase oncogenes. Nature. 1985;318:385–8.

    Article  CAS  PubMed  Google Scholar 

  16. Park M, Dean M, Kaul K, Braun MJ, Gonda MA, Vande, et al. Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proc Natl Acad Sci USA. 1987;84:6379–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, et al. Identification of the hepatocyte growth factor receptor as the c-Met proto-oncogene product. Science. 1991;251(Feb):802–4.

    Article  CAS  PubMed  Google Scholar 

  18. Jücker M, Günther A, Gradl G, Fonatsch C, Krueger G, Diehl V, et al. The Met/hepatocyte growth factor receptor (HGFR) gene is overexpressed in some cases of human leukemia and lymphoma. Leuk Res. 1994;18:7–16.

    Article  PubMed  Google Scholar 

  19. Mujtaba G, Schultz JM, Imtiaz A, Morell RJ, Friedman TB, Naz S. A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss. J Med Genet. 2015;52:548–52.

    Article  CAS  PubMed  Google Scholar 

  20. Gandino L, Longati P, Medico E, Prat M, Comoglio PM. Phosphorylation of ser 985 negatively regulates the hepatocyte growth factor receptor kinase. J Biol Chem. 1994;269:1815–20.

    Article  CAS  PubMed  Google Scholar 

  21. Kadoyama K, Funakoshi H, Ohya-Shimada W, Nakamura T, Matsumoto K, Matsuyama S, et al. Disease-dependent reciprocal phosphorylation of serine and tyrosine residues of c-Met/HGF receptor contributes disease retardation of a transgenic mouse model of ALS. Neurosci Res. 2009;65:194–200.

    Article  CAS  PubMed  Google Scholar 

  22. Nakayama M, Sakai K, Yamashita A, Nakamura T, Suzuki Y, Matsumoto K. Met/HGF receptor activation is regulated by juxtamembrane Ser985 phosphorylation in hepatocytes. Cytokine. 2013;62:446–52.

    Article  CAS  PubMed  Google Scholar 

  23. Peschard P, Fournier TM, Lamorte L, Naujokas MA, Band H, Langdon WY, et al. Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein. Mol Cell. 2001;8:995–1004.

    Article  CAS  PubMed  Google Scholar 

  24. Rodrigues GA, Park M. Autophosphorylation modulates the kinase activity and oncogenic potential of the Met receptor tyrosine kinase. Oncogene. 1994;9:2019–27.

    CAS  PubMed  Google Scholar 

  25. Suzuki M, Shiraha H, Fujikawa T, Takaoka N, Ueda N, Nakanishi Y, et al. Des-gamma-carboxy prothrombin is a potential autologous growth factor for hepatocellular carcinoma. J Biol Chem. 2005;280:6409–15.

    Article  CAS  PubMed  Google Scholar 

  26. Fan G, Zhang S, Gao Y, Greer PA, Tonks NK. HGF-independent regulation of MET and GAB1 by nonreceptor tyrosine kinase FER potentiates metastasis in ovarian cancer. Genes Dev. 2016;30:1542–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Corso S, Giordano S. Cell-autonomous and non-cell-autonomous mechanisms of HGF/MET-driven resistance to targeted therapies: from basic research to a clinical perspective. Cancer Discov. 2013;3:978–92.

    Article  CAS  PubMed  Google Scholar 

  28. Conrotto P, Corso S, Gamberini S, Comoglio PM, Giordano S. Interplay between scatter factor receptors and B plexins controls invasive growth. Oncogene. 2004;23:5131–7.

    Article  CAS  PubMed  Google Scholar 

  29. Chang L, Hu Y, Fu Y, Zhou T, You J, Du J, et al. Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells. Acta Pharm Sin B. 2019;9:484–95.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Wang H, Rao B, Lou J, Li J, Liu Z, Li A, et al. The function of the HGFc-Met axis in hepatocellular carcinoma. Front Cell Dev Biol. 2020;8:55.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997;16:68–73.

    Article  CAS  PubMed  Google Scholar 

  32. Ma PC, Jagadeeswaran R, Jagadeesh S, Tretiakova MS, Nallasura V, Fox EA, et al. Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res. 2005;65:1479–88.

    Article  CAS  PubMed  Google Scholar 

  33. Ma PC, Kijima T, Maulik G, Fox EA, Sattler M, Griffin JD, et al. c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res. 2003;63:6272–81.

    CAS  PubMed  Google Scholar 

  34. Krishnaswamy S, Kanteti R, Duke-Cohan JS, Loganathan S, Liu W, Ma PC, et al. Ethnic differences and functional analysis of MET mutations in lung cancer. Clin Cancer Res. 2009;15:5714–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lee JH, Han SU, Cho H, Jennings B, Gerrard B, Dean M, et al. A novel germ line juxtamembrane Met mutation in human gastric cancer. Oncogene. 2000;19:4947–53.

    Article  CAS  PubMed  Google Scholar 

  36. Ma PC, Tretiakova MS, MacKinnon AC, Ramnath N, Johnson C, Dietrich S, et al. Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer. 2008;47:1025–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Puri N, Ahmed S, Janamanchi V, Tretiakova M, Zumba O, Krausz T, et al. Met is a potentially new therapeutic target for treatment of human melanoma. Clin Cancer Res. 2007;13:2246–53.

    Article  CAS  PubMed  Google Scholar 

  38. Jagadeeswaran R, Ma PC, Seiwert TY, Jagadeeswaran S, Zumba O, Nallasura V, et al. Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma. Cancer Res. 2006;66:352–61.

    Article  CAS  PubMed  Google Scholar 

  39. Kong-Beltran M, Seshagiri S, Zha J, Zhu W, Bhawe K, Mendoza N, et al. Somatic mutations lead to an oncogenic deletion of met in lung cancer. Cancer Res. 2006;66:283–9.

    Article  CAS  PubMed  Google Scholar 

  40. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–50.

    Article  CAS  Google Scholar 

  41. Awad MM, Oxnard GR, Jackman DM, Savukoski DO, Hall D, Shivdasani P, et al. MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression. J Clin Oncol. 2016;34:721–30.

    Article  CAS  PubMed  Google Scholar 

  42. Gow CH, Hsieh MS, Wu SG, Shih JY. A comprehensive analysis of clinical outcomes in lung cancer patients harboring a MET exon 14 skipping mutation compared to other driver mutations in an East Asian population. Lung Cancer. 2017;103:82–89.

    Article  PubMed  Google Scholar 

  43. Liu X, Jia Y, Stoopler MB, Shen Y, Cheng H, Chen J, et al. Next-generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET gene mutations. J Clin Oncol. 2016;34:794–802.

    Article  CAS  PubMed  Google Scholar 

  44. Frampton GM, Ali SM, Rosenzweig M, Chmielecki J, Lu X, Bauer TM, et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 2015;5:850–9.

    Article  CAS  PubMed  Google Scholar 

  45. Navis AC, van Lith SA, van Duijnhoven SM, de Pooter M, Yetkin-Arik B, Wesseling P, et al. Identification of a novel MET mutation in high-grade glioma resulting in an auto-active intracellular protein. Acta Neuropathol. 2015;130:131–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061–8.

    Article  CAS  Google Scholar 

  47. Asaoka Y, Tada M, Ikenoue T, Seto M, Imai M, Miyabayashi K, et al. Gastric cancer cell line Hs746T harbors a splice site mutation of c-Met causing juxtamembrane domain deletion. Biochem Biophys Res Commun. 2010;394:1042–6.

    Article  CAS  PubMed  Google Scholar 

  48. Umeki K, Shiota G, Kawasaki H. Clinical significance of c-Met oncogene alterations in human colorectal cancer. Oncology. 1999;56:314–21.

    Article  CAS  PubMed  Google Scholar 

  49. Tong CY, Hui AB, Yin XL, Pang JC, Zhu XL, Poon WS, et al. Detection of oncogene amplifications in medulloblastomas by comparative genomic hybridization and array-based comparative genomic hybridization. J Neurosurg. 2004;100:187–93.

    CAS  PubMed  Google Scholar 

  50. Soman NR, Correa P, Ruiz BA, Wogan GN. The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions. Proc Natl Acad Sci USA. 1991;88:4892–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846.

    Article  CAS  PubMed  Google Scholar 

  52. Bao ZS, Chen HM, Yang MY, Zhang CB, Yu K, Ye WL, et al. RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas. Genome Res. 2014;24:1765–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. International Cancer Genome Consortium PedBrain Tumor Project. Recurrent MET fusion genes represent a drug target in pediatric glioblastoma. Nat Med. 2016;22:1314–20.

    Article  CAS  Google Scholar 

  54. Kong LR, Mohamed Salleh NAB, Ong RW, Tan TZ, Syn NL, Goh RM, et al. A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma. Nat Commun. 2020;11:1556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–43.

    Article  CAS  PubMed  Google Scholar 

  56. Skoulidis F, Heymach JV. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat Rev Cancer. 2019;19:495–509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  58. Xie Q, Bradley R, Kang L, Koeman J, Ascierto ML, Worschech A, et al. Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma. Proc Natl Acad Sci USA. 2012;109:570–5.

    Article  PubMed  Google Scholar 

  59. Cheng F, Guo D. MET in glioma: signaling pathways and targeted therapies. J Exp Clin Cancer Res. 2019;38:270.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Smolen GA, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H, et al. Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc Natl Acad Sci USA. 2006;103:2316–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3:347–61.

    Article  PubMed  Google Scholar 

  62. Daniel SK, Sullivan KM, Labadie KP, Pillarisetty VG. Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma. Clin Transl Med. 2019;8:10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Goyal L, Muzumdar MD, Zhu AX. Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin Cancer Res. 2013;19:2310–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tavian D, De Petro G, Benetti A, Portolani N, Giulini SM, Barlati S. u-PA and c-MET mRNA expression is co-ordinately enhanced while hepatocyte growth factor mRNA is down-regulated in human hepatocellular carcinoma. Int J Cancer. 2000;87:644–9.

    Article  CAS  PubMed  Google Scholar 

  65. Wu F, Wu L, Zheng S, Ding W, Teng L, Wang Z, et al. The clinical value of hepatocyte growth factor and its receptor-c-Met for liver cancer patients with hepatectomy. Dig Liver Dis. 2006;38:490–7.

    Article  CAS  PubMed  Google Scholar 

  66. Kondo S, Ojima H, Tsuda H, Hashimoto J, Morizane C, Ikeda M, et al. Clinical impact of c-Met expression and its gene amplification in hepatocellular carcinoma. Int J Clin Oncol. 2013;18:207–13.

    Article  CAS  PubMed  Google Scholar 

  67. Lee SJ, Lee J, Sohn I, Mao M, Kai W, Park CK, et al. A survey of c-MET expression and amplification in 287 patients with hepatocellular carcinoma. Anticancer Res. 2013;33:5179–86.

    CAS  PubMed  Google Scholar 

  68. Harding JJ, Nandakumar S, Armenia J, Khalil DN, Albano M, Ly M, et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin Cancer Res. 2019;25:2116–26.

    Article  CAS  PubMed  Google Scholar 

  69. Nault JC, Martin Y, Caruso S, Hirsch TZ, Bayard Q, Calderaro J, et al. Clinical impact of genomic diversity from early to advanced hepatocellular carcinoma. Hepatology. 2020;71:164–82.

    Article  CAS  PubMed  Google Scholar 

  70. Davis IJ, McFadden AW, Zhang Y, Coxon A, Burgess TL, Wagner AJ, et al. Identification of the receptor tyrosine kinase c-Met and its ligand, hepatocyte growth factor, as therapeutic targets in clear cell sarcoma. Cancer Res. 2010;70:639–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Schöffski P, Wozniak A, Stacchiotti S, Rutkowski P, Blay JY, Lindner LH, et al. Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 ‘CREATE’. Ann Oncol. 2017;28:3000–8.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Taulli R, Scuoppo C, Bersani F, Accornero P, Forni PE, Miretti S, et al. Validation of met as a therapeutic target in alveolar and embryonal rhabdomyosarcoma. Cancer Res. 2006;66:4742–9.

    Article  CAS  PubMed  Google Scholar 

  73. Dai L, Trillo-Tinoco J, Cao Y, Bonstaff K, Doyle L, Del Valle L, et al. Targeting HGF/c-MET induces cell cycle arrest, DNA damage, and apoptosis for primary effusion lymphoma. Blood. 2015;126:2821–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Guan X. Cancer metastases: challenges and opportunities. Acta Pharm Sin B. 2015;5:402–18.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Zambelli A, Biamonti G, Amato A. HGF/c-Met signalling in the tumor microenvironment. Adv Exp Med Biol. 2021;1270:31–44.

    Article  CAS  PubMed  Google Scholar 

  76. Zhang Y, Gao X, Zhu Y, Kadel D, Sun H, Chen J, et al. The dual blockade of MET and VEGFR2 signaling demonstrates pronounced inhibition on tumor growth and metastasis of hepatocellular carcinoma. J Exp Clin Cancer Res. 2018;37:93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ciccarese C, Brunelli M, Montironi R, Fiorentino M, Iacovelli R, Heng D, et al. The prospect of precision therapy for renal cell carcinoma. Cancer Treat Rev. 2016;49:37–44.

    Article  CAS  PubMed  Google Scholar 

  78. Oyama T, Ichimura E, Sano T, Kashiwabara K, Fukuda T, Nakajima T. C-Met expression of thyroid tissue with special reference to papillary carcinoma. Pathol Int. 1998;48:763–8.

    Article  CAS  PubMed  Google Scholar 

  79. Scarpino S, Cancellario d’Alena F, Di Napoli A, Pasquini A, Marzullo A, Ruco LP. Increased expression of Met protein is associated with up-regulation of hypoxia inducible factor-1 (HIF-1) in tumour cells in papillary carcinoma of the thyroid. J Pathol. 2004;202:352–8.

    Article  CAS  PubMed  Google Scholar 

  80. Nakamura Y, Matsubara D, Goto A, Ota S, Sachiko O, Ishikawa S, et al. Constitutive activation of c-Met is correlated with c-Met overexpression and dependent on cell–matrix adhesion in lung adenocarcinoma cell lines. Cancer Sci. 2008;99:14–22.

    Article  CAS  PubMed  Google Scholar 

  81. Charytonowicz E, Cordon-Cardo C, Matushansky I, Ziman M. Alveolar rhabdomyosarcoma: is the cell of origin a mesenchymal stem cell? Cancer Lett. 2009;279:126–36.

    Article  CAS  PubMed  Google Scholar 

  82. Skrzypek K, Kusienicka A, Szewczyk B, Adamus T, Lukasiewicz E, Miekus K, et al. Constitutive activation of MET signaling impairs myogenic differentiation of rhabdomyosarcoma and promotes its development and progression. Oncotarget. 2015;6:31378–98.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Previdi S, Maroni P, Matteucci E, Broggini M, Bendinelli P, Desiderio MA. Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and beta-catenin/Wnt pathways. Eur J Cancer. 2010;46:1679–91.

    Article  CAS  PubMed  Google Scholar 

  84. Di Renzo MF, Olivero M, Giacomini A, Porte H, Chastre E, Mirossay L, et al. Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin Cancer Res. 1995;1:147–54.

    PubMed  Google Scholar 

  85. Yao JF, Li XJ, Yan LK, He S, Zheng JB, Wang XR, et al. Role of HGF/c-Met in the treatment of colorectal cancer with liver metastasis. J Biochem Mol Toxicol. 2019;33:e22316.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Du F, Li X, Feng W, Qiao C, Chen J, Jiang M, et al. SOX13 promotes colorectal cancer metastasis by transactivating SNAI2 and c-MET. Oncogene. 2020;39:3522–40.

    Article  CAS  PubMed  Google Scholar 

  87. Shen M, Zhao X, Zhao L, Shi L, An S, Huang G, et al. Met is involved in TIGAR-regulated metastasis of non-small-cell lung cancer. Mol Cancer. 2018;17:88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Michikoshi H, Nakamura T, Sakai K, Suzuki Y, Adachi E, Matsugo S, et al. α-Lipoic acid-induced inhibition of proliferation and met phosphorylation in human non-small cell lung cancer cells. Cancer Lett. 2013;335:472–8.

    Article  CAS  PubMed  Google Scholar 

  89. Miura Y, Kozuki Y, Yagasaki K. Potentiation of invasive activity of hepatoma cells by reactive oxygen species is mediated by autocrine/paracrine loop of hepatocyte growth factor. Biochem Biophys Res Commun. 2003;305:160–5.

    Article  CAS  PubMed  Google Scholar 

  90. Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol. 2015;17:351–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Huang X, Gan G, Wang X, Xu T, Xie W. The HGF-MET axis coordinates liver cancer metabolism and autophagy for chemotherapeutic resistance. Autophagy. 2019;15:1258–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Che L, Chi W, Qiao Y, Zhang J, Song X, Liu Y, et al. Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans. Gut. 2020;69:177–86.

    Article  CAS  PubMed  Google Scholar 

  93. Yan B, Jiang Z, Cheng L, Chen K, Zhou C, Sun L, et al. Paracrine HGF/c-MET enhances the stem cell-like potential and glycolysis of pancreatic cancer cells via activation of YAP/HIF-1α. Exp Cell Res. 2018;371:63–71.

    Article  CAS  PubMed  Google Scholar 

  94. Zhang Y, Nguyen TTT, Shang E, Mela A, Humala N, Mahajan A, et al. MET inhibition elicits PGC1α-dependent metabolic reprogramming in glioblastoma. Cancer Res. 2020;80:30–43.

    Article  CAS  PubMed  Google Scholar 

  95. Nassar D, Blanpain C. Cancer stem cells: basic concepts and therapeutic implications. Annu Rev Pathol. 2016;11:47–76.

    Article  CAS  PubMed  Google Scholar 

  96. Saygin C, Matei D, Majeti R, Reizes O, Lathia JD. Targeting cancer stemness in the clinic: from hype to hope. Cell Stem Cell. 2019;24:25–40.

    Article  CAS  PubMed  Google Scholar 

  97. Jeon HM, Lee J. MET: roles in epithelial-mesenchymal transition and cancer stemness. Ann Transl Med. 2017;5:5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445:106–10.

    Article  PubMed  CAS  Google Scholar 

  99. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65:10946–51.

    Article  CAS  PubMed  Google Scholar 

  101. Li Y, Li A, Glas M, Lal B, Ying M, Sang Y, et al. c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proc Natl Acad Sci USA. 2011;108:9951–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Vermeulen L, De Sousa EMF, van der Heijden M, Cameron K, de Jong JH, Borovski T, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010;12:468–76.

    Article  CAS  PubMed  Google Scholar 

  103. Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009;457:608–11.

    Article  CAS  PubMed  Google Scholar 

  104. Xing F, Liu Y, Wu SY, Wu K, Sharma S, Mo YY, et al. Loss of XIST in breast cancer activates MSN-c-Met and reprograms microglia via exosomal miRNA to promote brain metastasis. Cancer Res. 2018;78:4316–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Joo KM, Jin J, Kim E, Ho Kim K, Kim Y, Gu Kang B, et al. MET signaling regulates glioblastoma stem cells. Cancer Res. 2012;72:3828–38.

    Article  CAS  PubMed  Google Scholar 

  106. Rath P, Lal B, Ajala O, Li Y, Xia S, Kim J, et al. In vivo c-Met pathway inhibition depletes human glioma xenografts of tumor-propagating stem-like cells. Transl Oncol. 2013;6:104–11.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Flores-Téllez TN, Villa-Treviño S, Piña-Vázquez C. Road to stemness in hepatocellular carcinoma. World J Gastroenterol. 2017;23:6750–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Dang H, Steinway SN, Ding W, Rountree CB. Induction of tumor initiation is dependent on CD44s in c-Met+ hepatocellular carcinoma. BMC Cancer. 2015;15:161.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Huang WC, Tung SL, Chen YL, Chen PM, Chu PY. IFI44L is a novel tumor suppressor in human hepatocellular carcinoma affecting cancer stemness, metastasis, and drug resistance via regulating met/Src signaling pathway. BMC Cancer. 2018;18:609.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Peng H, Xue R, Ju Z, Qiu J, Wang J, Yan W, et al. Cancer-associated fibroblasts enhance the chemoresistance of CD73+ hepatocellular carcinoma cancer cells via HGF-Met-ERK1/2 pathway. Ann Transl Med. 2020;8:856.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Jahangiri A, Nguyen A, Chandra A, Sidorov MK, Yagnik G, Rick J, et al. Cross-activating c-Met/β1 integrin complex drives metastasis and invasive resistance in cancer. Proc Natl Acad Sci USA. 2017;114:E8685–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487:500–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hugo W, Shi H, Sun L, Piva M, Song C, Kong X, et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell. 2015;162:1271–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zhou L, XD, Sun M, Zhang X, German P, Bai S, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016;35:2687–97.

    Article  CAS  PubMed  Google Scholar 

  115. Shojaei F, Lee JH, Simmons BH, Wong A, Esparza CO, Plumlee PA, et al. HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res. 2010;70:10090–100.

    Article  CAS  PubMed  Google Scholar 

  116. Westover D, Zugazagoitia J, Cho BC, Lovly CM, Paz-Ares L. Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Ann Oncol. 2018;29:i10–i19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Wu YL, Cheng Y, Zhou J, Lu S, Zhang Y, Zhao J, et al. Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial. Lancet Respir Med. 2020;8:1132–43.

    Article  CAS  PubMed  Google Scholar 

  118. Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA. 2007;104:20932–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wang Y, Chen Z, Han X, Li J, Guo H, Shi J. Acquired MET D1228N mutations mediate crizotinib resistance in lung adenocarcinoma with ROS1 fusion: a case report. Oncologist. 2021;26:178–81.

    Article  PubMed  Google Scholar 

  120. De Bacco F, Luraghi P, Medico E, Reato G, Girolami F, Perera T, et al. Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer. J Natl Cancer Inst. 2011;103:645–61.

    Article  PubMed  CAS  Google Scholar 

  121. Aebersold DM, Landt O, Berthou S, Gruber G, Beer KT, Greiner RH, et al. Prevalence and clinical impact of Met Y1253D-activating point mutation in radiotherapy-treated squamous cell cancer of the oropharynx. Oncogene. 2003;22:8519–23.

    Article  CAS  PubMed  Google Scholar 

  122. Jankowski K, Kucia M, Wysoczynski M, Reca R, Zhao D, Trzyna E, et al. Both hepatocyte growth factor (HGF) and stromal-derived factor-1 regulate the metastatic behavior of human rhabdomyosarcoma cells, but only HGF enhances their resistance to radiochemotherapy. Cancer Res. 2003;63:7926–35.

    CAS  PubMed  Google Scholar 

  123. Kim JH, Kim HS, Kim BJ. Prognostic value of MET copy number gain in non-small-cell lung cancer: an updated meta-analysis. J Cancer. 2018;9:1836–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Vuong HG, Ho ATN, Altibi AMA, Nakazawa T, Katoh R, Kondo T. Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer - a systematic review and meta-analysis. Lung Cancer. 2018;123:76–82.

    Article  PubMed  Google Scholar 

  125. Pyo JS, Kang G, Cho WJ, Choi SB. Clinicopathological significance and concordance analysis of c-MET immunohistochemistry in non-small cell lung cancers: a meta-analysis. Pathol Res Pr. 2016;212:710–6.

    Article  CAS  Google Scholar 

  126. Wang F, Li S, Zhao Y, Yang K, Chen M, Niu H, et al. Predictive role of the overexpression for CXCR4, C-Met, and VEGF-C among breast cancer patients: a meta-analysis. Breast. 2016;28:45–53.

    Article  PubMed  Google Scholar 

  127. Yan S, Jiao X, Zou H, Li K. Prognostic significance of c-Met in breast cancer: a meta-analysis of 6010 cases. Diagn Pathol. 2015;10:62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Zagouri F, Bago-Horvath Z, Rössler F, Brandstetter A, Bartsch R, Papadimitriou CA, et al. High MET expression is an adverse prognostic factor in patients with triple-negative breast cancer. Br J Cancer. 2013;108:1100–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Liu Y, Yu XF, Zou J, Luo ZH. Prognostic value of c-Met in colorectal cancer: a meta-analysis. World J Gastroenterol. 2015;21:3706–10.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Lee SJ, Lee J, Park SH, Park JO, Lim HY, Kang WK, et al. c-MET overexpression in colorectal cancer: a poor prognostic factor for survival. Clin Colorectal Cancer. 2018;17:165–9.

    Article  PubMed  Google Scholar 

  131. Choi J, Lee HE, Lee HS, Han N, Kim MA, Kim WH. Evaluation of intratumoral and intertumoral heterogeneity of MET protein expression in gastric cancer. Appl Immunohistochem Mol Morphol. 2018;26:445–45.

    Article  CAS  PubMed  Google Scholar 

  132. Huang KH, Sung IC, Fang WL, Chi CW, Yeh TS, Lee HC, et al. Correlation between HGF/c-Met and Notch1 signaling pathways in human gastric cancer cells. Oncol Rep. 2018;40:294–302.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Catenacci DV, Ang A, Liao WL, Shen J, O’Day E, Loberg RD, et al. MET tyrosine kinase receptor expression and amplification as prognostic biomarkers of survival in gastroesophageal adenocarcinoma. Cancer. 2017;123:1061–70.

    Article  CAS  PubMed  Google Scholar 

  134. Ren JL, Wu HF, Wang WJ, Hu GM, Gu B, Zhang M, et al. C-Met as a potential novel prognostic marker in squamous cell carcinoma and adenocarcinoma of esophagus: evidence from a meta-analysis. Panminerva Med. 2017;59:97–106.

    Article  PubMed  Google Scholar 

  135. Szturz P, Budíková M, Vermorken JB, Horová I, Gál B, Raymond E, et al. Prognostic value of c-MET in head and neck cancer: a systematic review and meta-analysis of aggregate data. Oral Oncol. 2017;74:68–76.

    Article  PubMed  Google Scholar 

  136. Vsiansky V, Gumulec J, Raudenska M, Masarik M. Prognostic role of c-Met in head and neck squamous cell cancer tissues: a meta-analysis. Sci Rep. 2018;8:10370.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Kim JH, Kim HS, Kim BJ, Lee J, Jang HJ. Prognostic value of c-Met overexpression in pancreatic adenocarcinoma: a meta-analysis. Oncotarget. 2017;8:73098–104.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Kim JH, Kim HS, Kim BJ, Jang HJ, Lee J. Prognostic value of c-Met overexpression in hepatocellular carcinoma: a meta-analysis and review. Oncotarget. 2017;8:90351–7.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Kim JH, Kim BJ, Kim HS. Clinicopathological impacts of high c-Met expression in renal cell carcinoma: a meta-analysis and review. Oncotarget. 2017;8:75478–87.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Gibney GT, Aziz SA, Camp RL, Conrad P, Schwartz BE, Chen CR, et al. c-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma. Ann Oncol. 2013;24:343–9.

    Article  CAS  PubMed  Google Scholar 

  141. Schiefer AI, Mesteri I, Berghoff AS, Haitel A, Schmidinger M, Preusser M, et al. Evaluation of tyrosine kinase receptors in brain metastases of clear cell renal cell carcinoma reveals c-Met as a negative prognostic factor. Histopathology. 2015;67:799–805.

    Article  PubMed  Google Scholar 

  142. Peng J, Qi S, Wang P, Li W, Liu C, Li F. Diagnosis and prognostic significance of c-Met in cervical cancer: a meta-analysis. Dis Markers. 2016;2016:6594016.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Lux A, Kahlert C, Grützmann R, Pilarsky C. c-Met and PD-L1 on circulating exosomes as diagnostic and prognostic markers for pancreatic cancer. Int J Mol Sci. 2019;20:3305.

    Article  CAS  PubMed Central  Google Scholar 

  144. Tsuji T, Sakamori Y, Ozasa H, Yagi Y, Ajimizu H, Yasuda Y, et al. Clinical impact of high serum hepatocyte growth factor in advanced non-small cell lung cancer. Oncotarget. 2017;8:71805–16.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Park DJ, Yoon C, Thomas N, Ku GY, Janjigian YY, Kelsen DP, et al. Prognostic significance of targetable angiogenic and growth factors in patients undergoing resection for gastric and gastroesophageal junction cancers. Ann Surgical Oncol. 2014;21:1130–7.

    Article  Google Scholar 

  146. Zhang Y, Wu JZ, Yang YQ, Ma R, Zhang JY, Feng JF. Expression of growth‑regulated oncogene‑1, hepatocyte growth factor, platelet‑derived growth factor‑AA and soluble E‑selectin and their association with high‑risk human papillomavirus infection in squamous cell carcinoma of the uterine cervix. Mol Med Rep. 2014;10:1013–24.

    Article  CAS  PubMed  Google Scholar 

  147. Liang QL, Mo ZY, Wang P, Li X, Liu ZX, Zhou ZM. The clinical value of serum hepatocyte growth factor levels in patients undergoing primary radiotherapy for glioma: effect on progression-free survival. Med Oncol. 2014;31:122.

    Article  PubMed  CAS  Google Scholar 

  148. Kubo Y, Fukushima S, Inamori Y, Tsuruta M, Egashira S, Yamada-Kanazawa S, et al. Serum concentrations of HGF are correlated with response to anti-PD-1 antibody therapy in patients with metastatic melanoma. J Dermatol Sci. 2019;93:33–40.

    Article  CAS  PubMed  Google Scholar 

  149. Saltarella I, Morabito F, Giuliani N, Terragna C, Omedè P, Palumbo A, et al. Prognostic or predictive value of circulating cytokines and angiogenic factors for initial treatment of multiple myeloma in the GIMEMA MM0305 randomized controlled trial. J Hematol Oncol. 2019;12:4.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Gupta A, Karakiewicz PI, Roehrborn CG, Lotan Y, Zlotta AR, Shariat SF. Predictive value of plasma hepatocyte growth factor/scatter factor levels in patients with clinically localized prostate cancer. Clin Cancer Res. 2008;14:7385–90.

    Article  CAS  PubMed  Google Scholar 

  151. Kim H, Youk J, Yang Y, Kim TY, Min A, Ham HS, et al. Prognostic implication of serum hepatocyte growth factor in stage II/III breast cancer patients who received neoadjuvant chemotherapy. J Cancer Res Clin Oncol. 2016;142:707–14.

    Article  CAS  PubMed  Google Scholar 

  152. van den Bent M, Azaro A, De Vos F, Sepulveda J, Yung WKA, Wen PY, et al. A phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma. J Neurooncol. 2020;146:79–89.

    Article  PubMed  CAS  Google Scholar 

  153. Wu YL, Zhang L, Kim DW, Liu X, Lee DH, Yang JC, et al. Phase Ib/II study of capmatinib (INC280) plus gefitinib after failure of epidermal growth factor receptor (EGFR) inhibitor therapy in patients with EGFR-mutated, MET factor-dysregulated non–small-cell lung cancer. J Clin Oncol. 2018;36:3101–9.

    Article  CAS  PubMed  Google Scholar 

  154. Wolf J, Seto T, Han JY, Reguart N, Garon EB, Groen HJM, et al. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. Engl J Med. 2020;383:944–57.

    Article  CAS  Google Scholar 

  155. Moro-Sibilot D, Cozic N, Pérol M, Mazières J, Otto J, Souquet PJ, et al. Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSé phase II trial. Ann Oncol. 2019;30:1985–91.

    Article  CAS  PubMed  Google Scholar 

  156. Aparicio T, Cozic N, de la Fouchardière C, Meriaux E, Plaza J, Mineur L. et al.The activity of crizotinib in chemo-refractory MET-amplified esophageal and gastric adenocarcinomas: results from the AcSé-crizotinib program.Target Oncol . 2021;16:381–8.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Ou SH, Kwak EL, Siwak-Tapp C, Dy J, Bergethon K, Clark JW, et al. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol. 2011;6:942–6.

    Article  PubMed  Google Scholar 

  158. Drilon A, Clark JW, Weiss J, Ou SI, Camidge DR, Solomon, et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat Med. 2020;26:47–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl J Med. 2013;368:2385–94.

    Article  CAS  PubMed  Google Scholar 

  160. Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N. Engl J Med. 2014;371:2167–77.

    Article  PubMed  CAS  Google Scholar 

  161. Solomon BJ, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, et al. Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-mutation-positive non-small-cell lung cancer. J Clin Oncol. 2018;36:2251–8.

    Article  CAS  PubMed  Google Scholar 

  162. Wu YL, Lu S, Lu Y, Zhou J, Shi YK, Sriuranpong V, et al. Results of Profile 1029, a phase III comparison of first- line crizotinib versus chemotherapy in East Asian patients with ALK-positive advanced non-small cell lung cancer. J Thorac Oncol. 2018;13:1539–48.

    Article  PubMed  Google Scholar 

  163. Paik PK, Felip E, Veillon R, Sakai H, Cortot AB, Garassino MC, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N. Engl J Med. 2020;383:931–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Burbridge MF, Bossard CJ, Saunier C, Fejes I, Bruno A, Leonce S, et al. S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab. Mol Cancer Ther. 2013;12:1749–62.

    Article  CAS  PubMed  Google Scholar 

  165. Rodon J, Postel-Vinay S, Hollebecque A, Nuciforo P, Azaro A, Cattan V, et al. First-in-human phase I study of oral S49076, a unique MET/AXL/FGFR inhibitor, in advanced solid tumours. Eur J Cancer. 2017;81:142–50.

    Article  CAS  PubMed  Google Scholar 

  166. Bertran-Alamillo J, Cattan V, Schoumacher M, Codony-Servat J, Giménez-Capitán A, Cantero F, et al. AURKB as a target in non-small cell lung cancer with acquired resistance to anti-EGFR therapy. Nat Commun. 2019;10:1812.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Park K, Chang GC, Curigliano G, Lim WT, Soo RA, Molina-Vila MA, et al. Phase I results of S49076 plus gefitinib in patients with EGFR TKI-resistant non-small cell lung cancer harbouring MET/AXL dysregulation. Lung Cancer. 2021;155:127–35.

    Article  PubMed  Google Scholar 

  168. Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011;29:2660–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013;31:412–9.

    Article  CAS  PubMed  Google Scholar 

  170. Kelley RK, Verslype C, Cohn AL, Yang TS, Su WC, Burris H, et al. Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study. Ann Oncol. 2017;28:528–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Wakelee HA, Gettinger S, Engelman J, Jänne PA, West H, Subramaniam DS, et al. A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharm. 2017;79:923–32.

    Article  CAS  Google Scholar 

  172. Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35:591–7.

    Article  CAS  PubMed  Google Scholar 

  173. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N. Engl J Med. 2015;373:1814–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17:917–27.

    Article  CAS  PubMed  Google Scholar 

  175. Hofmann F, Hwang EC, Lam TB, Bex A, Yuan Y, Marconi LS, et al. Targeted therapy for metastatic renal cell carcinoma. Cochrane Database Syst Rev. 2020;10:CD012796.

    PubMed  Google Scholar 

  176. Choueiri TK, Albiges L, Powles T, Scheffold C, Wang F, Motzer R. A phase III study (COSMIC-313) of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) of intermediate or poor risk. J Clin Oncol. 2020;38:TPS767.

    Article  Google Scholar 

  177. Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016;34:3005–13.

    Article  CAS  PubMed  Google Scholar 

  178. Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Schlumberger M, Elisei R, Müller S, Schöffski P, Brose M, Shah M, et al. Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Ann Oncol. 2017;28:2813–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Engstrom LD, Aranda R, Lee M, Tovar EA, Essenburg CJ, Madaj Z, et al. Glesatinib exhibits antitumor activity in lung cancer models and patients harboring MET exon 14 mutations and overcomes mutation-mediated resistance to type I MET inhibitors in nonclinical models. Clin Cancer Res. 2017;23:6661–72.

    Article  CAS  PubMed  Google Scholar 

  181. Roohullah A, Cooper A, Lomax AJ, Aung J, Barge A, Chow L, et al. A phase I trial to determine safety and pharmacokinetics of ASLAN002, an oral MET superfamily kinase inhibitor, in patients with advanced or metastatic solid cancers. Invest New Drugs. 2018;36:886–94.

    Article  CAS  PubMed  Google Scholar 

  182. Doi T, Matsubara N, Kawai A, Naka N, Takahashi S, Uemura H, et al. Phase I study of TAS-115, a novel oral multi-kinase inhibitor, in patients with advanced solid tumors. Invest New Drugs. 2020;38:1175–85.

    Article  CAS  PubMed  Google Scholar 

  183. Penuel E, Li C, Parab V, Burton L, Cowan KJ, Merchant M, et al. HGF as a circulating biomarker of onartuzumab treatment in patients with advanced solid tumors. Mol Cancer Ther. 2013;12:1122–30.

    Article  CAS  PubMed  Google Scholar 

  184. Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem. 2011;54:6342–63.

    Article  CAS  PubMed  Google Scholar 

  185. Drilon AE, Camidge DR, Ou S-HI, Clark JW, Socinski MA, Weiss J, et al. Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC). J Clin Oncol. 2016;34:108.

    Article  Google Scholar 

  186. Puccini A, Marín-Ramos NI, Bergamo F, Schirripa M, Lonardi S, Lenz HJ, et al. Safety and tolerability of c-MET Inhibitors in cancer. Drug Saf. 2019;42:211–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Baltschukat S, Engstler BS, Huang A, Hao HX, Tam A, Wang HQ, et al. Capmatinib (INC280) is active against models of non–small cell lung cancer and other cancer types with defined mechanisms of MET activation. Clin Cancer Res. 2019;25:3164–75.

    Article  CAS  PubMed  Google Scholar 

  188. Marona P, Górka J, Kotlinowski J, Majka M, Jura J, Miekus K. C-Met as a key factor responsible for sustaining undifferentiated phenotype and therapy resistance in renal carcinomas. Cells. 2019;8:272.

    Article  CAS  PubMed Central  Google Scholar 

  189. Li A, Yang JJ, Zhang XC, Zhang Z, Su J, Gou LY, et al. Acquired MET Y1248H and D1246N mutations mediate resistance to MET inhibitors in non-small cell lung cancer. Clin Cancer Res. 2017;23:4929–37.

    Article  CAS  PubMed  Google Scholar 

  190. Recondo G, Bahcall M, Spurr LF, Che J, Ricciuti B, Leonardi GC, et al. Molecular mechanisms of acquired resistance to MET tyrosine kinase inhibitors in patients with MET exon 14-mutant NSCLC. Clin Cancer Res. 2020;26:2615–25.

    Article  CAS  PubMed  Google Scholar 

  191. Li H, Li CW, Li X, Ding Q, Guo L, Liu S, et al. MET inhibitors promote liver tumor evasion of the immune response by stabilizing PDL1. Gastroenterology. 2019;156:1849–.e1813.

    Article  CAS  PubMed  Google Scholar 

  192. Maulik G, Kijima T, Ma PC, Ghosh SK, Lin J, Shapiro GI, et al. Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer. Clin Cancer Res. 2002;8:620–7.

    CAS  PubMed  Google Scholar 

  193. Antonia SJ, López-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17:883–95.

    Article  CAS  PubMed  Google Scholar 

  194. Ready N, Farago AF, de Braud F, Atmaca A, Hellmann MD, Schneider JG, et al. Third- line nivolumab monotherapy in recurrent SCLC: CheckMate 032. J Thorac Oncol. 2019;14:237–44.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

J.P. designed the review, wrote, and revised the manuscript with input from J.F., X.S., Z.L., L.D., X.L., X.F., and J.P. The literature search was performed and analyzed by J.F., X.S., Z.L., L.D., X.L., X.F., and J.P. The figures of the review were mainly painted by J.F., X.F., L.D., and X.L. A major part of Table 1 was completed by J.P. and J.F.; X.F. participated in revising the review critically for the important intellectual content. All authors have read and approved the manuscript.

Funding

This work has been supported by the National Natural Science Foundation of China (No. 81602631), the Guangdong Natural Science Foundation of China (No. 2016A030310280), the Students’ Laboratory Open Project of Guangzhou Medical University (No. C195015021), 2017 Elite Talents Training Plan of the Third Affiliated Hospital of Guangzhou Medical University (J.P.), and Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation: “Climbing Program” Special Funds (No. pdjh2020b0490).

Author information

Author notes

  1. These authors contributed equally: Jianjiang Fu, Xiaorui Su, Zhihua Li

Authors and Affiliations

  1. Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Jianjiang Fu, Xiaorui Su, Xiawei Liu, Xuancheng Feng & Juan Peng

  2. The Third Clinical School of Guangzhou Medical University, Guangzhou, China

    Jianjiang Fu, Xiaorui Su, Zhihua Li, Xiawei Liu, Xuancheng Feng & Juan Peng

  3. Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China

    Jianjiang Fu, Xiaorui Su, Zhihua Li, Xiawei Liu, Xuancheng Feng & Juan Peng

  4. Department of Fetal Medicine and Prenatal Diagnosis, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Zhihua Li

  5. Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China

    Ling Deng

Authors
  1. Jianjiang Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaorui Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhihua Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ling Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiawei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xuancheng Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Juan Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xuancheng Feng or Juan Peng.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fu, J., Su, X., Li, Z. et al. HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence. Oncogene 40, 4625–4651 (2021). https://doi.org/10.1038/s41388-021-01863-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-021-01863-w

Search

Advanced search

Quick links