Review Article | Published:

Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy

Nature Reviews Cancervolume 18pages341358 (2018) | Download Citation

Abstract

The MET oncogene encodes an unconventional receptor tyrosine kinase with pleiotropic functions: it initiates and sustains neoplastic transformation when genetically altered (‘oncogene addiction’) and fosters cancer cell survival and tumour dissemination when transcriptionally activated in the context of an adaptive response to adverse microenvironmental conditions (‘oncogene expedience’). Moreover, MET is an intrinsic modulator of the self-renewal and clonogenic ability of cancer stem cells (‘oncogene inherence’). Here, we provide the latest findings on MET function in cancer by focusing on newly identified genetic abnormalities in tumour cells and recently described non-mutational MET activities in stromal cells and cancer stem cells. We discuss how MET drives cancer clonal evolution and progression towards metastasis, both ab initio and under therapeutic pressure. We then elaborate on the use of MET inhibitors in the clinic with a critical appraisal of failures and successes. Ultimately, we advocate a rationale to improve the outcome of anti-MET therapies on the basis of thorough consideration of the entire spectrum of MET-mediated biological responses, which implicates adequate patient stratification, meaningful biomarkers and appropriate clinical end points.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

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

Nature Reviews Cancer thanks G. Vande Woude, K. Matsumoto and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Candiolo Cancer Institute: http://www.ircc.it/

COSMIC catalogue of human mutations in cancer: http://cancer.sanger.ac.uk/cosmic

Report from Aveo Pharmaceuticals Inc.: https://www.sec.gov/Archives/edgar/data/1325879/000119312516706645/d249918d8k.htm

US National Institutes of Health — ClinicalTrials.gov: https://clinicaltrials.gov/

References

  1. 1.

    Trusolino, L., Bertotti, A. & Comoglio, P. M. MET signalling: principles and functions in development, organ regeneration and cancer. Nat. Rev. Mol. Cell Biol. 11, 834–848 (2010).

  2. 2.

    Trusolino, L. & Comoglio, P. M. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat. Rev. Cancer 2, 289–300 (2002).

  3. 3.

    Boccaccio, C. & Comoglio, P. M. Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat. Rev. Cancer 6, 637–645 (2006).

  4. 4.

    Christofori, G. New signals from the invasive front. Nature 441, 444–450 (2006).

  5. 5.

    Ye, X. & Weinberg, R. A. Epithelial-mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol. 25, 675–686 (2015).

  6. 6.

    Bottaro, D. P. et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251, 802–804 (1991).

  7. 7.

    Naldini, L. et al. Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. EMBO J. 10, 2867–2878 (1991).

  8. 8.

    Nakamura, T., Nawa, K. & Ichihara, A. Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochem. Biophys. Res. Commun. 122, 1450–1459 (1984).

  9. 9.

    Stoker, M., Gherardi, E., Perryman, M. & Gray, J. Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature 327, 239–242 (1987).

  10. 10.

    Birchmeier, C., Birchmeier, W., Gherardi, E. & Vande Woude, G. F. Met, metastasis, motility and more. Nat. Rev. Mol. Cell Biol. 4, 915–925 (2003).

  11. 11.

    Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).

  12. 12.

    Shibue, T. & Weinberg, R. A. E. M. T. CSCs, and drug resistance: the mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 14, 611–629 (2017). This is a comprehensive Review discussing the relationship between the stemness and invasive phenotypes in cancer and its therapeutic implications.

  13. 13.

    Scheel, C., Onder, T., Karnoub, A. & Weinberg, R. A. Adaptation versus selection: the origins of metastatic behavior. Cancer Res. 67, 11476–11479 (2007).

  14. 14.

    Di Renzo, M. F. et al. Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene 19, 1547–1555 (2000).

  15. 15.

    Comoglio, P. M., Giordano, S. & Trusolino, L. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat. Rev. Drug Discov. 7, 504–516 (2008).

  16. 16.

    Gherardi, E., Birchmeier, W., Birchmeier, C. & Vande, W. G. Targeting MET in cancer: rationale and progress. Nat. Rev. Cancer 12, 89–103 (2012).

  17. 17.

    Corso, S. et al. Silencing the MET oncogene leads to regression of experimental tumors and metastases. Oncogene 27, 684–693 (2008).

  18. 18.

    Pennacchietti, S. et al. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3, 347–361 (2003).

  19. 19.

    Boccaccio, C., Gaudino, G., Gambarotta, G., Galimi, F. & Comoglio, P. M. Hepatocyte growth factor (HGF) receptor expression is inducible and is part of the delayed-early response to HGF. J. Biol. Chem. 269, 12846–12851 (1994).

  20. 20.

    Bhowmick, N. A., Neilson, E. G. & Moses, H. L. Stromal fibroblasts in cancer initiation and progression. Nature 432, 332–337 (2004).

  21. 21.

    Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).

  22. 22.

    Michieli, P. et al. Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. Cancer Cell 6, 61–73 (2004).

  23. 23.

    Hayward, N. K. et al. Whole-genome landscapes of major melanoma subtypes. Nature 545, 175–180 (2017).

  24. 24.

    Ponzetto, C. et al. c-Met is amplified but not mutated in a cell line with an activated met tyrosine kinase. Oncogene 6, 553–559 (1991).

  25. 25.

    Jeffers, M. et al. Activating mutations for the met tyrosine kinase receptor in human cancer. Proc. Natl Acad. Sci. USA 94, 11445–11450 (1997).

  26. 26.

    Snuderl, M. et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 20, 810–817 (2011). This study provides evidence that, in individual glioblastomas, MET, EGFR and PDGFR genes are amplified in different cells in a mutually exclusive fashion, implying that inhibition of each individual receptor alone can result in a selective advantage for subclones harbouring amplification of another.

  27. 27.

    Turke, A. B. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17, 77–88 (2010). This study shows that subclones harbouring MET amplification pre-exist in lung cancers with EGFR mutations and are positively selected by treatment with EGFR inhibitors.

  28. 28.

    Arteaga, C. L. & Engelman, J. A. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25, 282–303 (2014).

  29. 29.

    Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).

  30. 30.

    Bardelli, A. et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov. 3, 658–673 (2013). This study shows that MET amplification is a mechanism of resistance to anti-EGFR therapy in metastatic colorectal cancer, as an alternative to mutations in KRAS.

  31. 31.

    Bertotti, A. et al. The genomic landscape of response to EGFR blockade in colorectal cancer. Nature 526, 263–267 (2015).

  32. 32.

    Pietrantonio, F. et al. MET-driven resistance to dual EGFR and BRAF blockade may be overcome by switching from EGFR to MET inhibition in BRAF-mutated colorectal cancer. Cancer Discov. 6, 963–971 (2016).

  33. 33.

    Cepero, V. MET and KRAS gene amplification mediates acquired resistance to MET tyrosine kinase inhibitors. Cancer Res. 70, 7580–7590 (2010).

  34. 34.

    Henry, R. E. et al. Acquired savolitinib resistance in non-small cell lung cancer arises via multiple mechanisms that converge on MET-independent mTOR and MYC activation. Oncotarget 7, 57651–57670 (2016).

  35. 35.

    Kwak, E. L. et al. Molecular heterogeneity and receptor coamplification drive resistance to targeted therapy in MET-amplified esophagogastric cancer. Cancer Discov. 5, 1271–1281 (2015).

  36. 36.

    Bahcall, M. et al. Acquired MET D1228V mutation and resistance to MET inhibition in lung cancer. Cancer Discov. 6, 1334–1341 (2016).

  37. 37.

    Gandino, L., Longati, P., Medico, E., Prat, M. & Comoglio, P. M. Phosphorylation of serine 985 negatively regulates the hepatocyte growth factor receptor kinase. J. Biol. Chem. 269, 1815–1820 (1994).

  38. 38.

    Nakayama, M. et al. Met/HGF receptor activation is regulated by juxtamembrane Ser985 phosphorylation in hepatocytes. Cytokine 62, 446–452 (2013).

  39. 39.

    Peschard, P. 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 8, 995–1004 (2001).

  40. 40.

    Petrelli, A. et al. The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met. Nature 416, 187–190 (2002).

  41. 41.

    Weidner, K. M., Sachs, M., Riethmacher, D. & Birchmeier, W. Mutation of juxtamembrane tyrosine residue 1001 suppresses loss-of- function mutations of the met receptor in epithelial cells. Proc. Natl Acad. Sci. USA 92, 2597–2601 (1995).

  42. 42.

    Ma, P. C. et al. c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res. 63, 6272–6281 (2003).

  43. 43.

    Lee, C. C. & Yamada, K. M. Identification of a novel type of alternative splicing of a tyrosine kinase receptor. Juxtamembrane deletion of the c-met protein kinase C serine phosphorylation regulatory site. J. Biol. Chem. 269, 19457–19461 (1994).

  44. 44.

    Frampton, G. M. 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. 5, 850–859 (2015).

  45. 45.

    Ma, P. C. 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. 65, 1479–1488 (2005).

  46. 46.

    Kong-Beltran, M. et al. Somatic mutations lead to an oncogenic deletion of met in lung cancer. Cancer Res. 66, 283–289 (2006).

  47. 47.

    Vigna, E., Gramaglia, D., Longati, P., Bardelli, A. & Comoglio, P. M. Loss of the exon encoding the juxtamembrane domain is essential for the oncogenic activation of TPR-MET. Oncogene 18, 4275–4281 (1999).

  48. 48.

    Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).

  49. 49.

    Awad, M. M. 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. 34, 721–730 (2016).

  50. 50.

    Tong, J. H. et al. MET amplification and exon 14 splice site mutation define unique molecular subgroups of non-small cell lung carcinoma with poor prognosis. Clin. Cancer Res. 22, 3048–3056 (2016).

  51. 51.

    Liu, X. et al. Next-generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET Gene Mutations. J. Clin. Oncol. 34, 794–802 (2016).

  52. 52.

    Paik, P. K. et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov. 5, 842–849 (2015). References 44 and 52 are the first studies to systematically analyse the prevalence of MET exon 14 deletion across tumour types, finding the highest frequency in lung cancer. These two studies also show that MET inhibition induces durable responses in patients harbouring such an alteration.

  53. 53.

    Lee, J. et al. Gastrointestinal malignancies harbor actionable MET exon 14 deletions. Oncotarget 6, 28211–28222 (2015).

  54. 54.

    Soman, N. R., Correa, P., Ruiz, B. A. & Wogan, G. N. The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions. Proc. Natl Acad. Sci. USA 88, 4892–4896 (1991).

  55. 55.

    Stransky, N., Cerami, E., Schalm, S., Kim, J. L. & Lengauer, C. The landscape of kinase fusions in cancer. Nat. Commun. 5, 4846 (2014).

  56. 56.

    Bao, Z. S. et al. RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas. Genome Res. 24, 1765–1773 (2014).

  57. 57.

    International Cancer Genome Consortium PedBrain Tumor Project. Recurrent MET fusion genes represent a drug target in pediatric glioblastoma. Nat. Med. 22, 1314–1320 (2016).

  58. 58.

    Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013).

  59. 59.

    Navis, A. C. et al. Identification of a novel MET mutation in high-grade glioma resulting in an auto-active intracellular protein. Acta Neuropathol. 130, 131–144 (2015).

  60. 60.

    Gambarotta, G., Pistoi, S., Giordano, S., Comoglio, P. M. & Santoro, C. Structure and inducible regulation of the human MET promoter. J. Biol. Chem. 269, 12852–12857 (1994).

  61. 61.

    Chen, Q., Seol, D. W., Carr, B. & Zarnegar, R. Co-expression and regulation of Met and Ron proto-oncogenes in human hepatocellular carcinoma tissues and cell lines. Hepatology 26, 59–66 (1997).

  62. 62.

    Hwang, C. I. et al. Wild-type p53 controls cell motility and invasion by dual regulation of MET expression. Proc. Natl Acad. Sci. USA 108, 14240–14245 (2011).

  63. 63.

    Epstein, J. A., Shapiro, D. N., Cheng, J., Lam, P. Y. & Maas, R. L. Pax3 modulates expression of the c-Met receptor during limb muscle development. Proc. Natl Acad. Sci. USA 93, 4213–4218 (1996).

  64. 64.

    Kubic, J. D., Little, E. C., Lui, J. W., Iizuka, T. & Lang, D. PAX3 and ETS1 synergistically activate MET expression in melanoma cells. Oncogene 34, 4964–4974 (2015).

  65. 65.

    Gambarotta, G. et al. Ets up-regulates MET transcription. Oncogene 13, 1911–1917 (1996).

  66. 66.

    Finkbeiner, M. R. et al. Profiling YB-1 target genes uncovers a new mechanism for MET receptor regulation in normal and malignant human mammary cells. Oncogene 28, 1421–1431 (2009).

  67. 67.

    De Bacco, F. et al. Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer. J. Natl Cancer Inst. 103, 645–661 (2011).

  68. 68.

    Zarnegar, R. Regulation of HGF and HGFR gene expression. EXS 74, 33–49 (1995).

  69. 69.

    Bigatto, V. et al. TNF-alpha promotes invasive growth through the MET signaling pathway. Mol. Oncol. 9, 377–388 (2015).

  70. 70.

    Sennino, B., Ishiguro-Oonuma, T., Schriver, B. J., Christensen, J. G. & McDonald, D. M. Inhibition of c-Met reduces lymphatic metastasis in RIP-Tag2 transgenic mice. Cancer Res. 73, 3692–3703 (2013).

  71. 71.

    Pàez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220–231 (2009).

  72. 72.

    Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009).

  73. 73.

    Sennino, B. et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2, 270–287 (2012). This study shows that anti-angiogenic therapy can promote invasion and metastasis, an outcome that can be prevented by concomitant MET inhibition.

  74. 74.

    Rigamonti, N. et al. Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep. 8, 696–706 (2014).

  75. 75.

    Bill, R. et al. Nintedanib is a highly effective therapeutic for neuroendocrine carcinoma of the pancreas (PNET) in the Rip1Tag2 transgenic mouse model. Clin. Cancer Res. 21, 4856–4867 (2015).

  76. 76.

    Jubb, A. M., Oates, A. J., Holden, S. & Koeppen, H. Predicting benefit from anti-angiogenic agents in malignancy. Nat. Rev. Cancer 6, 626–635 (2006).

  77. 77.

    McIntyre, A. & Harris, A. L. Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality. EMBO Mol. Med. 7, 368–379 (2015).

  78. 78.

    Lu, K. V. et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22, 21–35 (2012). This study provides evidence that VEGF inhibition can disrupt a physical interaction between VEGFR2 and MET and enable pro-invasive activities in tumour cells.

  79. 79.

    De Bacco, F. et al. MET inhibition overcomes radiation resistance of glioblastoma stem-like cells. EMBO Mol. Med. 8, 550–568 (2016). This study shows, in a preclinical model, that MET inhibition can circumvent the recognized radioresistance of glioblastoma stem cells by enhancing the DDR.

  80. 80.

    Du, Y. et al. Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors. Nat. Med. 22, 194–201 (2016). This study shows that MET inhibitors suppress a mechanism of resistance to PARP inhibitors and provides preclinical evidence for combination therapy in breast and ovarian cancer.

  81. 81.

    De Palma, M., Biziato, D. & Petrova, T. V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 17, 457–474 (2017).

  82. 82.

    McCourt, M., Wang, J. H., Sookhai, S. & Redmond, H. P. Activated human neutrophils release hepatocyte growth factor/scatter factor. Eur. J. Surg. Oncol. 27, 396–403 (2001).

  83. 83.

    Galimi, F. et al. Hepatocyte growth factor is a regulator of monocyte-macrophage function. J. Immunol. 166, 1241–1247 (2001).

  84. 84.

    Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).

  85. 85.

    Wilson, T. R. et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487, 505–509 (2012).

  86. 86.

    Harbinski, F. et al. Rescue screens with secreted proteins reveal compensatory potential of receptor tyrosine kinases in driving cancer growth. Cancer Discov. 2, 948–959 (2012). References 84–86 highlight the ability of HGF present in the microenvironment to protect cancer cells from the actions of BRAF or tyrosine kinase inhibitors.

  87. 87.

    Yano, S. et al. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res. 68, 9479–9487 (2008).

  88. 88.

    Pennacchietti, S. et al. Microenvironment-derived HGF overcomes genetically determined sensitivity to anti-MET drugs. Cancer Res. 74, 6598–6609 (2014).

  89. 89.

    Nakamura, T., Matsumoto, K., Kiritoshi, A. & Tano, Y. Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells: in vitro analysis of tumor-stromal interactions. Cancer Res. 57, 3305–3313 (1997).

  90. 90.

    Kawaguchi, M. & Kataoka, H. Mechanisms of hepatocyte growth factor activation in cancer tissues. Cancers 6, 1890–1904 (2014).

  91. 91.

    Zarnegar, R. & Michalopoulos, G. K. The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis. J. Cell Biol. 129, 1177–1180 (1995).

  92. 92.

    Ilangumaran, S., Villalobos-Hernandez, A., Bobbala, D. & Ramanathan, S. The hepatocyte growth factor (HGF)-MET receptor tyrosine kinase signaling pathway: Diverse roles in modulating immune cell functions. Cytokine 82, 125–139 (2016).

  93. 93.

    Flaquer, M. et al. Hepatocyte growth factor gene therapy enhances infiltration of macrophages and may induce kidney repair in db/db mice as a model of diabetes. Diabetologia 55, 2059–2068 (2012).

  94. 94.

    Molnarfi, N., Benkhoucha, M., Bjarnadóttir, K., Juillard, C. & Lalive, P. H. Interferon-β induces hepatocyte growth factor in monocytes of multiple sclerosis patients. PLoS ONE 7, e49882 (2012).

  95. 95.

    Coudriet, G. M., He, J., Trucco, M., Mars, W. M. & Piganelli, J. D. Hepatocyte growth factor modulates interleukin-6 production in bone marrow derived macrophages: implications for inflammatory mediated diseases. PLoS ONE 5, e15384 (2010).

  96. 96.

    Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 (2010).

  97. 97.

    Tu, H. et al. CXCR4 and SDF-1 production are stimulated by hepatocyte growth factor and promote glioma cell invasion. Onkologie 32, 331–336 (2009).

  98. 98.

    Holland, J. D. et al. Combined Wnt/β-catenin, Met, and CXCL12/CXCR4 signals characterize basal breast cancer and predict disease outcome. Cell Rep. 5, 1214–1227 (2013).

  99. 99.

    Sánchez-Martín, L. et al. The chemokine CXCL12 regulates monocyte-macrophage differentiation and RUNX3 expression. Blood 117, 88–97 (2011).

  100. 100.

    Balkwill, F. Cancer and the chemokine network. Nat. Rev. Cancer 4, 540–550 (2004).

  101. 101.

    Baek, J. H., Birchmeier, C., Zenke, M. & Hieronymus, T. The HGF receptor/Met tyrosine kinase is a key regulator of dendritic cell migration in skin immunity. J. Immunol. 189, 1699–1707 (2012).

  102. 102.

    Okunishi, K. et al. A novel role of hepatocyte growth factor as an immune regulator through suppressing dendritic cell function. J. Immunol. 175, 4745–4753 (2005).

  103. 103.

    Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat. Rev. Cancer 5, 263–274 (2005).

  104. 104.

    Yamaura, K. et al. Suppression of acute and chronic rejection by hepatocyte growth factor in a murine model of cardiac transplantation: induction of tolerance and prevention of cardiac allograft vasculopathy. Circulation 110, 1650–1657 (2004).

  105. 105.

    Futamatsu, H. et al. Hepatocyte growth factor ameliorates the progression of experimental autoimmune myocarditis: a potential role for induction of T helper 2 cytokines. Circ. Res. 96, 823–830 (2005).

  106. 106.

    Benkhoucha, M. et al. Hepatocyte growth factor limits autoimmune neuroinflammation via glucocorticoid-induced leucine zipper expression in dendritic cells. J. Immunol. 193, 2743–2752 (2014).

  107. 107.

    Singhal, E. & Sen, P. Hepatocyte growth factor-induced c-Src-phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway inhibits dendritic cell activation by blocking IκB kinase activity. Int. J. Biochem. Cell Biol. 43, 1134–1146 (2011).

  108. 108.

    Singhal, E., Kumar, P. & Sen, P. A novel role for Bruton’s tyrosine kinase in hepatocyte growth factor-mediated immunoregulation of dendritic cells. J. Biol. Chem. 286, 32054–32063 (2011).

  109. 109.

    Motz, G. T. & Coukos, G. Deciphering and reversing tumor immune suppression. Immunity 39, 61–73 (2013).

  110. 110.

    Finisguerra, V. et al. MET is required for the recruitment of anti-tumoural neutrophils. Nature 522, 349–353 (2015).

  111. 111.

    Mishalian, I. et al. Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression. Cancer Immunol. Immunother. 62, 1745–1756 (2013).

  112. 112.

    Glodde, N. et al. Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy. Immunity 47, 789–802.e789 (2017).

  113. 113.

    Théry, C., Zitvogel, L. & Amigorena, S. Exosomes: composition, biogenesis and function. Nat. Rev. Immunol. 2, 569–579 (2002).

  114. 114.

    Peinado, H. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18, 883–891 (2012).

  115. 115.

    White, A. C. & Lowry, W. E. Refining the role for adult stem cells as cancer cells of origin. Trends Cell Biol. 25, 11–20 (2015).

  116. 116.

    Ishikawa, T. et al. Hepatocyte growth factor/c-met signaling is required for stem-cell-mediated liver regeneration in mice. Hepatology 55, 1215–1226 (2012).

  117. 117.

    Kitade, M. et al. Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling. Genes Dev. 27, 1706–1717 (2013).

  118. 118.

    Gastaldi, S. et al. Met signaling regulates growth, repopulating potential and basal cell-fate commitment of mammary luminal progenitors: implications for basal-like breast cancer. Oncogene 32, 1428–1440 (2013).

  119. 119.

    Nicoleau, C. et al. Endogenous hepatocyte growth factor is a niche signal for subventricular zone neural stem cell amplification and self-renewal. Stem Cells 27, 408–419 (2009).

  120. 120.

    Joosten, S. P. J. et al. MET Signaling Mediates Intestinal Crypt-Villus Development, Regeneration, and Adenoma Formation and Is Promoted by Stem Cell CD44 Isoforms. Gastroenterology 153, 1040–1053.e4 (2017).

  121. 121.

    Luraghi, P. et al. MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors. Cancer Res. 74, 1857–1869 (2014).

  122. 122.

    Li, C. et al. c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology 141, 2218–2227 (2011).

  123. 123.

    De Bacco, F. et al. The MET Oncogene Is a Functional Marker of a Glioblastoma Stem Cell Subtype. Cancer Res. 72, 4537–4550 (2012).

  124. 124.

    Li, Y. et al. c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proc. Natl Acad. Sci. USA 108, 9951–9956 (2011). This study shows that MET sustains the stem cell phenotype in glioblastoma through induction of reprogramming transcription factors.

  125. 125.

    Joo, K. M. et al. MET signaling regulates glioblastoma stem cells. Cancer Res. 72, 3828–3838 (2012).

  126. 126.

    Tamase, A. et al. Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin. Proc. Natl Acad. Sci. USA 106, 17163–17168 (2009).

  127. 127.

    Kentsis, A. et al. Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia. Nat. Med. 18, 1118–1122 (2012).

  128. 128.

    Gohda, E. et al. Biological and immunological properties of human hepatocyte growth factor from plasma of patients with fulminant hepatic failure. Biochim. Biophys. Acta 1053, 21–26 (1990).

  129. 129.

    Kopp, J. L., Grompe, M. & Sander, M. Stem cells versus plasticity in liver and pancreas regeneration. Nat. Cell Biol. 18, 238–245 (2016).

  130. 130.

    Schmidt, C. et al. Scatter factor/hepatocyte growth factor is essential for liver development. Nature 373, 699–702 (1995).

  131. 131.

    Suzuki, A. et al. Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver. J. Cell Biol. 156, 173–184 (2002).

  132. 132.

    Duncan, A. W., Dorrell, C. & Grompe, M. Stem cells and liver regeneration. Gastroenterology 137, 466–481 (2009).

  133. 133.

    Visvader, J. E. & Stingl, J. Mammary stem cells and the differentiation hierarchy: current status and perspectives. Genes Dev. 28, 1143–1158 (2014).

  134. 134.

    Graveel, C. R. et al. Met induces diverse mammary carcinomas in mice and is associated with human basal breast cancer. Proc. Natl Acad. Sci. USA 106, 12909–12914 (2009).

  135. 135.

    Charafe-Jauffret, E. et al. Gene expression profiling of breast cell lines identifies potential new basal markers. Oncogene 25, 2273–2284 (2006).

  136. 136.

    Molyneux, G. et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7, 403–417 (2010).

  137. 137.

    Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).

  138. 138.

    Morel, A. P. et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS ONE 3, e2888 (2008).

  139. 139.

    Todaro, M. et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 1, 389–402 (2007).

  140. 140.

    Vermeulen, L. et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc. Natl Acad. Sci. USA 105, 13427–13432 (2008).

  141. 141.

    Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 12, 468–476 (2010).

  142. 142.

    Luraghi, P. et al. A molecularly annotated model of patient-derived colon cancer stem-like cells to assess genetic and non-genetic mechanisms of resistance to anti-EGFR therapy. Clin. Cancer Res. 24, 807–820 (2018).

  143. 143.

    Date, S. & Sato, T. Mini-gut organoids: reconstitution of the stem cell niche. Annu. Rev. Cell Dev. Biol. 31, 269–289 (2015).

  144. 144.

    Zeilstra, J. et al. Deletion of the WNT target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis. Cancer Res. 68, 3655–3661 (2008).

  145. 145.

    Zoller, M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat. Rev. Cancer 11, 254–267 (2011).

  146. 146.

    Orian-Rousseau, V., Chen, L., Sleeman, J. P., Herrlich, P. & Ponta, H. CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev. 16, 3074–3086 (2002).

  147. 147.

    Todaro, M. et al. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell 14, 342–356 (2014).

  148. 148.

    Alcantara Llaguno, S. R. & Parada, L. F. Cell of origin of glioma: biological and clinical implications. Br. J. Cancer 115, 1445–1450 (2016).

  149. 149.

    Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98–110 (2010).

  150. 150.

    Anido, J. et al. TGF-beta receptor inhibitors target the CD44(high)/Id1(high) glioma-initiating cell population in human glioblastoma. Cancer Cell 18, 655–668 (2010).

  151. 151.

    Bao, S. et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006).

  152. 152.

    McDermott, U. et al. Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc. Natl Acad. Sci. USA 104, 19936–19941 (2007).

  153. 153.

    Benvenuti, S. et al. An ‘in-cell trial’ to assess the efficacy of a monovalent anti-MET antibody as monotherapy and in association with standard cytotoxics. Mol. Oncol. 8, 378–388 (2014).

  154. 154.

    Lennerz, J. K. et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J. Clin. Oncol. 29, 4803–4810 (2011).

  155. 155.

    Spigel, D. R. et al. Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung. J. Clin. Oncol. 35, 412–420 (2017).

  156. 156.

    Scagliotti, G. et al. Phase III multinational, randomized, double-blind, placebo-controlled study of tivantinib (ARQ 197) plus erlotinib versus erlotinib alone in previously treated patients with locally advanced or metastatic nonsquamous non-small-cell lung cancer. J. Clin. Oncol. 33, 2667–2674 (2015).

  157. 157.

    Basilico, C. et al. Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET. Clin. Cancer Res. 19, 2381–2392 (2013).

  158. 158.

    Calles, A. et al. Tivantinib (ARQ 197) efficacy is independent of MET inhibition in non-small-cell lung cancer cell lines. Mol. Oncol. 9, 260–269 (2015).

  159. 159.

    Maemondo, M. et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362, 2380–2388 (2010).

  160. 160.

    Garassino, M. C. et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 14, 981–988 (2013).

  161. 161.

    Surati, M., Patel, P., Peterson, A. & Salgia, R. Role of MetMAb (OA-5D5) in c-MET active lung malignancies. Expert Opin. Biol. Ther. 11, 1655–1662 (2011).

  162. 162.

    Catenacci, D. V. T. et al. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 18, 1467–1482 (2017).

  163. 163.

    Ries, C. H. et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25, 846–859 (2014).

  164. 164.

    Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 (2013).

  165. 165.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02323126 (2017).

  166. 166.

    Tabassum, D. P. & Polyak, K. Tumorigenesis: it takes a village. Nat. Rev. Cancer 15, 473–483 (2015).

  167. 167.

    Siravegna, G., Marsoni, S., Siena, S. & Bardelli, A. Integrating liquid biopsies into the management of cancer. Nat. Rev. Clin. Oncol. 14, 116–120 (2017).

  168. 168.

    Wan, J. C. et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat. Rev. Cancer 17, 223–238 (2017).

  169. 169.

    Camidge, D. R. et al. Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC) [abstract]. J. Clin. Oncol. 32(Suppl.), 8001 (2014).

  170. 170.

    Crosetto, N., Bienko, M. & van Oudenaarden, A. Spatially resolved transcriptomics and beyond. Nat. Rev. Genet. 16, 57–66 (2015).

  171. 171.

    Skog, J. et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10, 1470–1476 (2008).

  172. 172.

    Mazzone, M. et al. An uncleavable form of pro-scatter factor suppresses tumor growth and dissemination in mice. J. Clin. Invest. 114, 1418–1432 (2004).

  173. 173.

    Ponzetto, C. et al. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell 77, 261–271 (1994).

  174. 174.

    Boccaccio, C. et al. Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature 391, 285–288 (1998).

  175. 175.

    Schaeper, U. et al. Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses. J. Cell Biol. 149, 1419–1432 (2000).

  176. 176.

    Weidner, K. M. et al. Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature 384, 173–176 (1996).

  177. 177.

    Benvenuti, S. et al. Ron kinase transphosphorylation sustains MET oncogene addiction. Cancer Res. 71, 1945–1955 (2011).

  178. 178.

    Viticchiè, G. & Muller, P. A. J. c-Met and other cell surface molecules: interaction, activation and functional consequences. Biomedicines 3, 46–70 (2015).

  179. 179.

    Gentile, A., Lazzari, L., Benvenuti, S., Trusolino, L. & Comoglio, P. M. Ror1 is a pseudokinase that is crucial for Met-driven tumorigenesis. Cancer Res. 71, 3132–3141 (2011).

  180. 180.

    Orian-Rousseau, V. CD44 acts as a signaling platform controlling tumor progression and metastasis. Front. Immunol. 6, 154 (2015).

  181. 181.

    Giordano, S. et al. The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat. Cell Biol. 4, 720–724 (2002).

  182. 182.

    Trusolino, L., Bertotti, A. & Comoglio, P. M. A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth. Cell 107, 643–654 (2001).

  183. 183.

    Franco, M. et al. The tetraspanin CD151 is required for Met-dependent signaling and tumor cell growth. J. Biol. Chem. 285, 38756–38764 (2010).

  184. 184.

    Thorpe, L. M., Yuzugullu, H. & Zhao, J. J. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat. Rev. Cancer 15, 7–24 (2015).

  185. 185.

    Ménard, L., Parker, P. J. & Kermorgant, S. Receptor tyrosine kinase c-Met controls the cytoskeleton from different endosomes via different pathways. Nat. Commun. 5, 3907 (2014).

  186. 186.

    Varadhachary, G. R. & Raber, M. N. Cancer of unknown primary site. N. Engl. J. Med. 371, 757–765 (2014).

  187. 187.

    Jeffers, M. et al. The mutationally activated Met receptor mediates motility and metastasis. Proc. Natl Acad. Sci. USA 95, 14417–14422 (1998).

  188. 188.

    Rong, S., Segal, S., Anver, M., Resau, J. H. & Vande, W. G. F. Invasiveness and metastasis of NIH 3T3 cells induced by Met-hepatocyte growth factor/scatter factor autocrine stimulation. Proc. Natl Acad. Sci. USA 91, 4731–4735 (1994).

  189. 189.

    Jeffers, M., Rong, S., Anver, M. & Vande, W. G. F. Autocrine hepatocyte growth factor/scatter factor-Met signaling induces transformation and the invasive/metastastic phenotype in C127 cells. Oncogene 13, 853–856 (1996).

  190. 190.

    Gallego, M. I., Bierie, B. & Hennighausen, L. Targeted expression of HGF/SF in mouse mammary epithelium leads to metastatic adenosquamous carcinomas through the activation of multiple signal transduction pathways. Oncogene 22, 8498–8508 (2003).

  191. 191.

    Meiners, S., Brinkmann, V., Naundorf, H. & Birchmeier, W. Role of morphogenetic factors in metastasis of mammary carcinoma cells. Oncogene 16, 9–20 (1998).

  192. 192.

    Stella, G. M. et al. MET mutations in cancers of unknown primary origin (CUPs). Hum. Mutat. 32, 44–50 (2011).

  193. 193.

    Gherardi, E. et al. 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. USA 100, 12039–12044 (2003).

  194. 194.

    Stella, G. M. et al. MET mutations are associated with aggressive and radioresistant brain metastatic non-small-cell lung cancer. Neuro Oncol. 18, 598–599 (2016).

  195. 195.

    Lamszus, K., Laterra, J., Westphal, M. & Rosen, E. M. Scatter factor/hepatocyte growth factor (SF/HGF) content and function in human gliomas. Int. J. Dev. Neurosci. 17, 517–530 (1999).

  196. 196.

    Chaft, J. E. et al. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin. Cancer Res. 17, 6298–6303 (2011).

  197. 197.

    Kuriyama, Y. et al. Disease flare after discontinuation of crizotinib in anaplastic lymphoma kinase-positive lung cancer. Case Rep. Oncol. 6, 430–433 (2013).

  198. 198.

    Pupo, E. et al. Rebound effects caused by withdrawal of MET kinase inhibitor are quenched by a MET therapeutic antibody. Cancer Res. 76, 5019–5029 (2016).

  199. 199.

    Sangwan, V. et al. Regulation of the Met receptor-tyrosine kinase by the protein-tyrosine phosphatase 1B and T-cell phosphatase. J. Biol. Chem. 283, 34374–34383 (2008).

  200. 200.

    Stamos, J., Lazarus, R. A., Yao, X., Kirchhofer, D. & Wiesmann, C. Crystal structure of the HGF beta-chain in complex with the Sema domain of the Met receptor. EMBO J. 23, 2325–2335 (2004).

  201. 201.

    Gherardi, E. et al. Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc. Natl Acad. Sci. USA 103, 4046–4051 (2006).

  202. 202.

    Basilico, C., Arnesano, A., Galluzzo, M., Comoglio, P. M. & Michieli, P. A high affinity hepatocyte growth factor-binding site in the immunoglobulin-like region of Met. J. Biol. Chem. 283, 21267–21277 (2008).

  203. 203.

    Basilico, C. et al. Four individually druggable MET hotspots mediate HGF-driven tumor progression. J. Clin. Invest. 124, 3172–3186 (2014).

  204. 204.

    DiCara, D. M. et al. Characterization and structural determination of a new anti-MET function-blocking antibody with binding epitope distinct from the ligand binding domain. Sci. Rep. 7, 9000 (2017).

  205. 205.

    Park, M. et al. Mechanism of met oncogene activation. Cell 45, 895–904 (1986).

  206. 206.

    Ohuchida, K. et al. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res. 64, 3215–3222 (2004).

  207. 207.

    Wynn, T. A., Chawla, A. & Pollard, J. W. Macrophage biology in development, homeostasis and disease. Nature 496, 445–455 (2013).

  208. 208.

    DeNardo, D. G., Andreu, P. & Coussens, L. M. Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev. 29, 309–316 (2010).

  209. 209.

    Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 31, 563–604 (2013).

  210. 210.

    Coffelt, S. B., Wellenstein, M. D. & de Visser, K. E. Neutrophils in cancer: neutral no more. Nat. Rev. Cancer 16, 431–446 (2016).

  211. 211.

    D’Arcangelo, M. & Cappuzzo, F. Focus on the potential role of ficlatuzumab in the treatment of non-small cell lung cancer. Biologics 7, 61–68 (2013).

  212. 212.

    Liu, L. et al. LY2875358, a neutralizing and internalizing anti-MET bivalent antibody, inhibits HGF-dependent and HGF-independent MET activation and tumor growth. Clin. Cancer Res. 20, 6059–6070 (2014).

  213. 213.

    Hultberg, A. et al. Depleting MET-expressing tumor cells by ADCC provides a therapeutic advantage over inhibiting HGF/MET signaling. Cancer Res. 75, 3373–3383 (2015).

  214. 214.

    Lee, B. S. et al. Met degradation by SAIT301, a Met monoclonal antibody, reduces the invasion and migration of nasopharyngeal cancer cells via inhibition of EGR-1 expression. Cell Death Dis. 5, e1159 (2014).

  215. 215.

    Lee, J. M. et al. Cbl-independent degradation of Met: ways to avoid agonism of bivalent Met-targeting antibody. Oncogene 33, 34–43 (2014).

  216. 216.

    Waqar, S. N., Morgensztern, D. & Sehn, J. MET mutation associated with responsiveness to crizotinib. J. Thorac. Oncol. 10, e29–e31 (2015).

  217. 217.

    Mendenhall, M. A. & Goldman, J. W. MET-Mutated NSCLC with Major Response to Crizotinib. J. Thorac. Oncol. 10, e33–e34 (2015).

  218. 218.

    Mahjoubi, L., Gazzah, A., Besse, B., Lacroix, L. & Soria, J. C. A never-smoker lung adenocarcinoma patient with a MET exon 14 mutation (D1028N) and a rapid partial response after crizotinib. Invest. New Drugs 34, 397–398 (2016).

  219. 219.

    Chi, A. S. et al. Rapid radiographic and clinical improvement after treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-epithelial transition inhibitor. J. Clin. Oncol. 30, e30–e33 (2012).

  220. 220.

    Shah, M. A. et al. Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer. PLoS ONE 8, e54014 (2013).

  221. 221.

    Sequist, L. V. et al. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J. Clin. Oncol. 29, 3307–3315 (2011).

  222. 222.

    Yoshioka, H. et al. A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study). Ann. Oncol. 26, 2066–2072 (2015).

  223. 223.

    Schuler, M. H. et al. Phase (Ph) I study of the safety and efficacy of the cMET inhibitor capmatinib (INC280) in patients (pts) with advanced cMET + non-small cell lung cancer (NSCLC). J. Clin. Oncol. 34, 9067–9067 (2016).

  224. 224.

    Wu, Y.-L. et al. Phase (Ph) II safety and efficacy results of a single-arm ph ib/II study of capmatinib (INC280) + gefitinib in patients (pts) with EGFR-mutated (mut), cMET-positive (cMET+) non-small cell lung cancer (NSCLC). J. Clin. Oncol. 34, 9020–9020 (2016).

Download references

Acknowledgements

The authors thank J. M. Hughes for clinical trial database mining, L. Lanzetti for micrographs and M. Milan for scrutiny of MET mutations. The authors also thank A. Cignetto, D. Gramaglia and F. Natale for excellent assistance. Work in the authors’ laboratories is supported by the Italian Association for Cancer Research (‘Special Program Molecular Clinical Oncology 5 × 1000, N. 9970’ and investigator grants N. 15572 to P.M.C., N. 18532 to L.T. and N. 15709 and N. 19933 to C.B.); Fondazione Piemontese per la Ricerca sul Cancro-ONLUS (5 × 1000 Italian Ministry of Health 2011 and 2014); Italian Ministry of Health (Ricerca Corrente); Transcan, TACTIC; and Comitato per Albi98.

Author information

Affiliations

  1. Exploratory Research and Molecular Cancer Therapy, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy

    • Paolo M. Comoglio
  2. Translational Cancer Medicine, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy

    • Livio Trusolino
  3. Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy

    • Carla Boccaccio
  4. Department of Oncology, University of Torino Medical School, Candiolo, Italy

    • Livio Trusolino
    •  & Carla Boccaccio

Authors

  1. Search for Paolo M. Comoglio in:

  2. Search for Livio Trusolino in:

  3. Search for Carla Boccaccio in:

Contributions

P.M.C., L.T. and C.B. contributed equally to writing and reviewing the manuscript.

Competing interests

P.M.C. is co-founder and scientific adviser of Octimet Oncology NV and Metis Precision Medicine B-Corp. C.B. and L.T. declare no competing interests.

Corresponding author

Correspondence to Paolo M. Comoglio.

Electronic supplementary material

Glossary

Lung sarcomatoid tumours

A poorly differentiated non-small-cell lung carcinoma that contains a component of sarcoma-like cells (that is, cells that display traits of mesenchymal differentiation).

Interstitial pressure

The pressure of fluid that flows out of capillaries and fills the space between the vascular system and cells.

Progression-free survival

(PFS). The time elapsed between the initiation of treatment and the onset of disease progression; measured both during and after therapy.

Overall survival

(OS). The time elapsed between the initiation of treatment and the death of the patient.

Matrix metalloproteinases

(MMPs). Zinc-dependent proteolytic enzymes secreted by cancer cells and stromal cells; these proteases degrade extracellular matrix (ECM) components, which facilitates cancer cell invasion, and cleave cell membrane-bound or ECM-associated precursor forms of many growth factors, thereby activating them and increasing their bioavailability in the tumour microenvironment.

Exosomes

Small extracellular vesicles secreted by multiple cell types that can be internalized by other cells. The transfer of the exosomal cargo (RNAs and proteins) may induce functional modifications in the recipient cells.

Cholangiocarcinomas

A type of cancer arising in the epithelial lining of biliary ducts.

Liquid biopsies

The sampling and analysis of nucleic acids or other circulating tumour-derived materials (including cancer cells and exosomes) present in biological fluids.

Array comparative genomic hybridization

A molecular cytogenetic technique that utilizes competitive hybridization of differently labelled probes to compare gene copy number differences between two genomes.

In situ hybridization

A cytogenetic method that uses DNA or RNA probes to visualize complementary DNA or RNA sequences in tissue sections.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/s41568-018-0002-y