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.

Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges

A Corrigendum to this article was published on 23 January 2018

Key Points

  • Aberrant c-MET pathway activation occurs frequently in gastrointestinal tumours and can result from multiple mechanisms, including c-MET protein overexpression, MET amplification or enhanced transcription and/or aberrant autocrine or paracrine secretion of HGF

  • Activated c-MET signalling results in enhanced cancer cell proliferation, survival and invasion; furthermore, a complex network of signalling involving other receptors enhances the potency and endurance of c-MET downstream signalling

  • Elevated c-MET expression/amplification has been associated with a poor clinical outcome in patients with gastro-oesophageal tumours, although conflicting reports exist with respect to a prognostic role of c-MET in colorectal cancer

  • Structural studies of HGF and c-MET have yielded important results that paved the way for the development of anti-HGF and anti-c-MET monoclonal antibodies and specific or nonspecific c-MET tyrosine kinase inhibitors

  • In contrast to the initial phase II studies, the phase III trials failed to show any clinical benefit from anti-HGF or anti-c-MET therapies in gastrointestinal tumours, even in patients with c-MET-positive disease

  • Additional biomarkers should be sought, using techniques such as MET RNA in situ hybridization (ISH) and MET single/double silver ISH and 'omics'-based approaches to identify patients that are likely to derive maximal benefits from anti-HGF/c-MET therapies

Abstract

Data from many preclinical studies, including those using cellular models of colorectal, gastric, gastro-oesophageal and gastro-oesophageal junction cancers, indicate that the hepatocyte growth factor (HGF)–hepatocyte growth factor receptor (c-MET) pathway is vital for the growth, survival and invasive potential of gastrointestinal cancers. Following the availability of data from these various studies, and data on c-MET expression as a biomarker that indicates a poor prognosis in patients with gastrointestinal cancer and increased c-MET expression, inhibitors targeting this pathway have entered the clinic in the past decade. However, the design of clinical trials that incorporate the use of HGF/c-MET inhibitors in their most appropriate genetic and molecular context remains crucial. Recognizing and responding to this challenge, the European Commission funded Framework 7 MErCuRIC programme is running a biomarker-enriched clinical trial investigating the efficacy of combined c-MET/MEK inhibition in patients with RAS-mutant or RAS-wild-type metastatic colorectal cancer with aberrant c-MET expression. The design of this trial enables the continued refinement of the predictive biomarker and co-development of companion diagnostics. In this Review, we focus on advances in our understanding of inhibition of the HGF/c-MET pathway in patients with gastro-intestinal cancers, the prominent challenges facing the clinical translation and implementation of agents targeting HGF/c-MET, and discuss the various efforts, and associated obstacles to the discovery and validation of biomarkers that will enable patient stratification in this context.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The multidomain structure of c-MET and its ligand, HGF.
Figure 2: HGF/c-MET signalling pathway components, interaction network, and mechanisms of negative regulation.
Figure 3: Deregulation of the HGF/c-MET pathway in colorectal cancer and gastric cancer.
Figure 4: Stratification biomarkers to identify MET-dependent colorectal cancers (CRCs).
Figure 5: HGF/c-MET inhibitors in clinical trials.

References

  1. 1

    Guinney, J. et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21, 1350–1356 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).

  3. 3

    Van Schaeybroeck, S., Allen, W. L., Turkington, R. C. & Johnston, P. G. Implementing prognostic and predictive biomarkers in CRC clinical trials. Nat. Rev. Clin. Oncol. 8, 222–232 (2011).

    CAS  Google Scholar 

  4. 4

    Gomez-Martin, C. et al. A critical review of HER2-positive gastric cancer evaluation and treatment: from trastuzumab, and beyond. Cancer Lett. 351, 30–40 (2014).

    CAS  Google Scholar 

  5. 5

    Bardelli, A. et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov. 3, 658–673 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Van Schaeybroeck, S. et al. ADAM17-dependent c-MET–STAT3 signaling mediates resistance to MEK inhibitors in KRAS mutant colorectal cancer. Cell Rep. 7, 1940–1955 (2014).

    CAS  Google Scholar 

  7. 7

    Takeuchi, H. et al. c-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases. Clin. Cancer Res. 9, 1480–1488 (2003).

    CAS  Google Scholar 

  8. 8

    Blumenschein, G. R. Jr, Mills, G. B. & Gonzalez-Angulo, A. M. Targeting the hepatocyte growth factor-cMET axis in cancer therapy. J. Clin. Oncol. 30, 3287–3296 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Cooper, C. S. et al. Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 311, 29–33 (1984).

    CAS  Google Scholar 

  10. 10

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

    CAS  Google Scholar 

  11. 11

    Nakamura, T. et al. Molecular cloning and expression of human hepatocyte growth factor. Nature 342, 440–443 (1989).

    CAS  Google Scholar 

  12. 12

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

    CAS  Google Scholar 

  13. 13

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

    CAS  Google Scholar 

  14. 14

    Chmielowiec, J. et al. c-Met is essential for wound healing in the skin. J. Cell Biol. 177, 151–162 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Borowiak, M. et al. Met provides essential signals for liver regeneration. Proc. Natl Acad. Sci. USA 101, 10608–10613 (2004).

    CAS  Google Scholar 

  16. 16

    Boccaccio, C. & Comoglio, P. M. MET, a driver of invasive growth and cancer clonal evolution under therapeutic pressure. Curr. Opin. Cell Biol. 31, 98–105 (2014).

    CAS  Google Scholar 

  17. 17

    Di Renzo, M. F. et al. Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin. Cancer Res. 1, 147–154 (1995).

    CAS  Google Scholar 

  18. 18

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    El-Deiry, W. S. et al. Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites. Cancer Biol. Ther. 16, 1726–1737 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    De Oliveira, A. T. et al. MET Is highly expressed in advanced stages of colorectal cancer and indicates worse prognosis and mortality. Anticancer Res. 29, 4807–4811 (2009).

    Google Scholar 

  21. 21

    Liu, Y., Yu, X. F., Zou, J. & Luo, Z. H. Prognostic value of c-Met in colorectal cancer: a meta-analysis. World J. Gastroenterol. 21, 3706–3710 (2015).

    PubMed  PubMed Central  Google Scholar 

  22. 22

    Peng, Z. et al. Prognostic significance of MET amplification and expression in gastric cancer: a systematic review with meta-analysis. PLoS ONE 9, e84502 (2014).

    PubMed  PubMed Central  Google Scholar 

  23. 23

    Resnick, M. B., Routhier, J., Konkin, T., Sabo, E. & Pricolo, V. E. Epidermal growth factor receptor, c-MET, beta-catenin, and p53 expression as prognostic indicators in stage II colon cancer: a tissue microarray study. Clin. Cancer Res. 10, 3069–3075 (2004).

    CAS  Google Scholar 

  24. 24

    Koeppen, H. et al. Biomarker analyses from a placebo-controlled phase II study evaluating erlotinib+/−onartuzumab in advanced non-small cell lung cancer: MET expression levels are predictive of patient benefit. Clin. Cancer Res. 20, 4488–4498 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Cunningham, D. et al. Phase III, randomized, double-blind, multicenter, placebo (P)-controlled trial of rilotumumab (R) plus epirubicin, cisplatin and capecitabine (ECX) as first-line therapy in patients (pts) with advanced MET-positive (pos) gastric or gastroesophageal junction (G/GEJ) cancer: RILOMET-1 study [abstract]. J. Clin. Oncol. 33 (Suppl.), 4000 (2015).

    Google Scholar 

  26. 26

    Shah, M. A. et al. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: the METGastric randomized clinical trial. JAMA Oncol. http://dx.doi.org/10.1001/jamaoncol.2016.5580 (2016).

  27. 27

    Iveson, T. et al. Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study. Lancet Oncol. 15, 1007–1018 (2014).

    CAS  Google Scholar 

  28. 28

    Doi, T. et al. A phase 3, multicenter, randomized, double-blind, placebo-controlled study of rilotumumab in combination with cisplatin and capecitabine (CX) as first-line therapy for Asian patients (pts) with advanced MET-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma:the RILOMET-2 trial [abstract]. J. Clin. Oncol. 33 (Suppl. 3), TPS226 (2015).

    Google Scholar 

  29. 29

    Van Schaeybroeck, S. et al. MErCuRIC1: a phase I study of MEK1/2 inhibitor PD-0325901 with cMET inhibitor crizotinib in RASMT and RASWT (with aberrant c-MET) metastatic colorectal cancer (mCRC) patients [abstract]. J. Clin. Oncol. 33 (Suppl.), TPS3632 (2015).

    Google Scholar 

  30. 30

    Komada, M. et al. Proteolytic processing of the hepatocyte growth factor/scatter factor receptor by furin. FEBS Lett. 328, 25–29 (1993).

    CAS  Google Scholar 

  31. 31

    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).

    CAS  Google Scholar 

  32. 32

    Lokker, N. A. et al. Structure-function analysis of hepatocyte growth factor: identification of variants that lack mitogenic activity yet retain high affinity receptor binding. EMBO J. 11, 2503–2510 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Andermarcher, E., Surani, M. A. & Gherardi, E. Co-expression of the HGF/SF and c-met genes during early mouse embryogenesis precedes reciprocal expression in adjacent tissues during organogenesis. Dev. Genet. 18, 254–266 (1996).

    CAS  Google Scholar 

  34. 34

    Holmes, O. et al. Insights into the structure/function of hepatocyte growth factor/scatter factor from studies with individual domains. J. Mol. Biol. 367, 395–408 (2007).

    CAS  Google Scholar 

  35. 35

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

    CAS  Google Scholar 

  36. 36

    Pelicci, G. et al. The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein. Oncogene 10, 1631–1638 (1995).

    CAS  Google Scholar 

  37. 37

    Fixman, E. D., Fournier, T. M., Kamikura, D. M., Naujokas, M. A. & Park, M. Pathways downstream of Shc and Grb2 are required for cell transformation by the tpr-Met oncoprotein. J. Biol. Chem. 271, 13116–13122 (1996).

    CAS  Google Scholar 

  38. 38

    Zhang, Y. W., Wang, L. M., Jove, R. & Vande Woude, G. F. Requirement of Stat3 signaling for HGF/SF-Met mediated tumorigenesis. Oncogene 21, 217–226 (2002).

    CAS  Google Scholar 

  39. 39

    Sipeki, S. et al. Phosphatidylinositol 3-kinase contributes to Erk1/Erk2 MAP kinase activation associated with hepatocyte growth factor-induced cell scattering. Cell Signal. 11, 885–890 (1999).

    CAS  Google Scholar 

  40. 40

    Maroun, C. R. et al. The Gab1 PH domain is required for localization of Gab1 at sites of cell–cell contact and epithelial morphogenesis downstream from the met receptor tyrosine kinase. Mol. Cell. Biol. 19, 1784–1799 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Maroun, C. R., Naujokas, M. A., Holgado-Madruga, M., Wong, A. J. & Park, M. The tyrosine phosphatase SHP-2 is required for sustained activation of extracellular signal-regulated kinase and epithelial morphogenesis downstream from the met receptor tyrosine kinase. Mol. Cell. Biol. 20, 8513–8525 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Fan, S. et al. Role of NF-kappaB signaling in hepatocyte growth factor/scatter factor-mediated cell protection. Oncogene 24, 1749–1766 (2005).

    CAS  Google Scholar 

  43. 43

    Rahimi, N., Hung, W., Tremblay, E., Saulnier, R. & Elliott, B. c-Src kinase activity is required for hepatocyte growth factor-induced motility and anchorage-independent growth of mammary carcinoma cells. J. Biol. Chem. 273, 33714–33721 (1998).

    CAS  Google Scholar 

  44. 44

    Royal, I., Lamarche-Vane, N., Lamorte, L., Kaibuchi, K. & Park, M. Activation of cdc42, rac, PAK, and rho-kinase in response to hepatocyte growth factor differentially regulates epithelial cell colony spreading and dissociation. Mol. Biol. Cell 11, 1709–1725 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Lock, L. S., Royal, I., Naujokas, M. A. & Park, M. Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyrosine kinases. J. Biol. Chem. 275, 31536–31545 (2000).

    CAS  Google Scholar 

  46. 46

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

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    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).

    CAS  Google Scholar 

  48. 48

    Garcia-Guzman, M., Dolfi, F., Zeh, K. & Vuori, K. Met-induced JNK activation is mediated by the adapter protein Crk and correlates with the Gab1–Crk signaling complex formation. Oncogene 18, 7775–7786 (1999).

    CAS  Google Scholar 

  49. 49

    Gual, P. et al. Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis. Oncogene 19, 1509–1518 (2000).

    CAS  Google Scholar 

  50. 50

    Montagner, A. et al. A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation. J. Biol. Chem. 280, 5350–5360 (2005).

    CAS  Google Scholar 

  51. 51

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Orian-Rousseau, V. et al. Hepatocyte growth factor-induced Ras activation requires ERM proteins linked to both CD44v6 and F-actin. Mol. Biol. Cell 18, 76–83 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Conrotto, P., Corso, S., Gamberini, S., Comoglio, P. M. & Giordano, S. Interplay between scatter factor receptors and B plexins controls invasive growth. Oncogene 23, 5131–5137 (2004).

    CAS  Google Scholar 

  54. 54

    Conrotto, P. et al. Sema4D induces angiogenesis through Met recruitment by Plexin B1. Blood 105, 4321–4329 (2005).

    CAS  Google Scholar 

  55. 55

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

    CAS  Google Scholar 

  56. 56

    Bertotti, A., Comoglio, P. M. & Trusolino, L. Beta4 integrin activates a Shp2–Src signaling pathway that sustains HGF-induced anchorage-independent growth. J. Cell Biol. 175, 993–1003 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    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).

    CAS  Google Scholar 

  58. 58

    Carter, S., Urbe, S. & Clague, M. J. The met receptor degradation pathway: requirement for Lys48-linked polyubiquitin independent of proteasome activity. J. Biol. Chem. 279, 52835–52839 (2004).

    CAS  Google Scholar 

  59. 59

    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).

    CAS  Google Scholar 

  60. 60

    Hammond, D. E., Urbe, S., Vande Woude, G. F. & Clague, M. J. Down-regulation of MET, the receptor for hepatocyte growth factor. Oncogene 20, 2761–2770 (2001).

    CAS  Google Scholar 

  61. 61

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

    CAS  Google Scholar 

  62. 62

    Kermorgant, S. & Parker, P. J. Receptor trafficking controls weak signal delivery: a strategy used by c-Met for STAT3 nuclear accumulation. J. Cell Biol. 182, 855–863 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Nath, D., Williamson, N. J., Jarvis, R. & Murphy, G. Shedding of c-Met is regulated by crosstalk between a G-protein coupled receptor and the EGF receptor and is mediated by a TIMP-3 sensitive metalloproteinase. J. Cell Sci. 114, 1213–1220 (2001).

    CAS  Google Scholar 

  64. 64

    Foveau, B. et al. Down-regulation of the met receptor tyrosine kinase by presenilin-dependent regulated intramembrane proteolysis. Mol. Biol. Cell 20, 2495–2507 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

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

    CAS  Google Scholar 

  66. 66

    Lee, J. H. et al. A novel germ line juxtamembrane Met mutation in human gastric cancer. Oncogene 19, 4947–4953 (2000).

    CAS  Google Scholar 

  67. 67

    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).

    CAS  Google Scholar 

  68. 68

    Schmidt, L. et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat. Genet. 16, 68–73 (1997).

    CAS  Google Scholar 

  69. 69

    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).

    CAS  Google Scholar 

  70. 70

    Dulak, A. M. et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat. Genet. 45, 478–486 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Cancer Genome Atlas Research Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

  72. 72

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Kammula, U. S. et al. Molecular co-expression of the c-Met oncogene and hepatocyte growth factor in primary colon cancer predicts tumor stage and clinical outcome. Cancer Lett. 248, 219–228 (2007).

    CAS  Google Scholar 

  74. 74

    Toiyama, Y. et al. Co-expression of hepatocyte growth factor and c-Met predicts peritoneal dissemination established by autocrine hepatocyte growth factor/c-Met signaling in gastric cancer. Int. J. Cancer 130, 2912–2921 (2012).

    CAS  Google Scholar 

  75. 75

    Park, W. S. et al. Absence of mutations in the kinase domain of the Met gene and frequent expression of Met and HGF/SF protein in primary gastric carcinomas. APMIS 108, 195–200 (2000).

    CAS  Google Scholar 

  76. 76

    Zhao, J., Zhang, X. & Xin, Y. Up-regulated expression of Ezrin and c-Met proteins are related to the metastasis and prognosis of gastric carcinomas. Histol. Histopathol. 26, 1111–1120 (2011).

    CAS  Google Scholar 

  77. 77

    Fischer, O. M., Giordano, S., Comoglio, P. M. & Ullrich, A. Reactive oxygen species mediate Met receptor transactivation by G protein-coupled receptors and the epidermal growth factor receptor in human carcinoma cells. J. Biol. Chem. 279, 28970–28978 (2004).

    CAS  Google Scholar 

  78. 78

    Jo, M. et al. Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells. J. Biol. Chem. 275, 8806–8811 (2000).

    CAS  Google Scholar 

  79. 79

    Khoury, H. et al. HGF converts ErbB2/Neu epithelial morphogenesis to cell invasion. Mol. Biol. Cell 16, 550–561 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Bauer, T. W. et al. Regulatory role of c-Met in insulin-like growth factor-I receptor-mediated migration and invasion of human pancreatic carcinoma cells. Mol. Cancer Ther. 5, 1676–1682 (2006).

    CAS  Google Scholar 

  81. 81

    Salian-Mehta, S., Xu, M. & Wierman, M. E. AXL and MET crosstalk to promote gonadotropin releasing hormone (GnRH) neuronal cell migration and survival. Mol. Cell. Endocrinol. 374, 92–100 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Rong, S., Segal, S., Anver, M., Resau, J. H. & Vande Woude, 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).

    CAS  Google Scholar 

  83. 83

    Moshitch-Moshkovitz, S. et al. In vivo direct molecular imaging of early tumorigenesis and malignant progression induced by transgenic expression of GFP-Met. Neoplasia 8, 353–363 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Giordano, S. et al. A point mutation in the MET oncogene abrogates metastasis without affecting transformation. Proc. Natl Acad. Sci. USA 94, 13868–13872 (1997).

    CAS  Google Scholar 

  85. 85

    Taniguchi, K. et al. The relation between the growth patterns of gastric carcinoma and the expression of hepatocyte growth factor receptor (c-met), autocrine motility factor receptor, and urokinase-type plasminogen activator receptor. Cancer 82, 2112–2122 (1998).

    CAS  Google Scholar 

  86. 86

    Wu, X. et al. Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. Cancer Lett. 335, 128–135 (2013).

    CAS  Google Scholar 

  87. 87

    Amemiya, H. et al. c-Met expression in gastric cancer with liver metastasis. Oncology 63, 286–296 (2002).

    CAS  Google Scholar 

  88. 88

    Bradley, C. A. et al. Transcriptional upregulation of c-MET is associated with invasion and tumor budding in colorectal cancer. Oncotarget 7, 78921–78945 (2016).

    Google Scholar 

  89. 89

    Jiang, W. G., Lloyds, D., Puntis, M. C., Nakamura, T. & Hallett, M. B. Regulation of spreading and growth of colon cancer cells by hepatocyte growth factor. Clin. Exp. Metastasis 11, 235–242 (1993).

    CAS  Google Scholar 

  90. 90

    Sun, Y. L. et al. Expression of HGF and Met in human tissues of colorectal cancers: biological and clinical implications for synchronous liver metastasis. Int. J. Med. Sci. 10, 548–559 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Zeng, Z. S. et al. c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. Cancer Lett. 265, 258–269 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Gayyed, M. F., Abd El-Maqsoud, N. M., El- Hameed El-Heeny, A. A. & Mohammed, M. F. c-MET expression in colorectal adenomas and primary carcinomas with its corresponding metastases. J. Gastrointest. Oncol. 6, 618–627 (2015).

    PubMed  PubMed Central  Google Scholar 

  93. 93

    Zou, H. Y. et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 67, 4408–4417 (2007).

    CAS  Google Scholar 

  94. 94

    Lee, H. E. et al. MET in gastric carcinomas: comparison between protein expression and gene copy number and impact on clinical outcome. Br. J. Cancer 107, 325–333 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Nakajima, M. et al. The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer 85, 1894–1902 (1999).

    CAS  Google Scholar 

  96. 96

    Xu, Y. et al. Expression and clinical significance of c-Met in advanced esophageal squamous cell carcinoma. BMC Cancer 15, 6 (2015).

    PubMed  PubMed Central  Google Scholar 

  97. 97

    Fuse, N. et al. Prognostic impact of HER2, EGFR, and c-MET status on overall survival of advanced gastric cancer patients. Gastric Cancer 19, 183–191 (2016).

    CAS  Google Scholar 

  98. 98

    Schweiger, T. et al. Clinical impact of c-MET expression and mutational status in patients with colorectal cancer lung metastases. Eur. J. Cardiothorac. Surg. 49, 1103–1111 (2016).

    Google Scholar 

  99. 99

    Al-Maghrabi, J. et al. c-MET immunostaining in colorectal carcinoma is associated with local disease recurrence. BMC Cancer 15, 676 (2015).

    PubMed  PubMed Central  Google Scholar 

  100. 100

    Voutsina, A. et al. Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer. Mod. Pathol. 26, 302–313 (2013).

    CAS  Google Scholar 

  101. 101

    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. 3, 978–992 (2013).

    CAS  Google Scholar 

  102. 102

    Harbinski, F. et al. Rescue screens with secreted proteins reveal compensatory potential of receptor tyrosine kinases in driving cancer growth. CancerDiscov. 2, 948–959 (2012).

    CAS  Google Scholar 

  103. 103

    Chen, C. T. et al. MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells. Mol. Cancer Ther. 11, 660–669 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Kim, J. et al. Preexisting oncogenic events impact trastuzumab sensitivity in ERBB2-amplified gastroesophageal adenocarcinoma. J. Clin. Invest. 124, 5145–5158 (2014).

    PubMed  PubMed Central  Google Scholar 

  105. 105

    Liska, D., Chen, C. T., Bachleitner-Hofmann, T., Christensen, J. G. & Weiser, M. R. HGF rescues colorectal cancer cells from EGFR inhibition via MET activation. Clin. Cancer Res. 17, 472–482 (2011).

    CAS  Google Scholar 

  106. 106

    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).

    CAS  Google Scholar 

  107. 107

    Diaz, L. A. Jr, Sausen, M., Fisher, G. A. & Velculescu, V. E. Insights into therapeutic resistance from whole-genome analyses of circulating tumor DNA. Oncotarget 4, 1856–1857 (2013).

    PubMed  PubMed Central  Google Scholar 

  108. 108

    Carson, R. et al. HDAC inhibition overcomes acute resistance to MEK inhibition in BRAF-mutant colorectal cancer by downregulation of c-FLIPL. Clin. Cancer Res. 21, 3230–3240 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    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).

    CAS  Google Scholar 

  110. 110

    Li, Y. et al. c-Met targeting enhances the effect of irradiation and chemical agents against malignant colon cells harboring a KRAS mutation. PLoS ONE 9, e113186 (2014).

    PubMed  PubMed Central  Google Scholar 

  111. 111

    Burgess, T. L. et al. Biochemical characterization of AMG 102: a neutralizing, fully human monoclonal antibody to human and nonhuman primate hepatocyte growth factor. Mol. Cancer Ther. 9, 400–409 (2010).

    CAS  Google Scholar 

  112. 112

    Rosen, P. J. et al. A phase Ib study of AMG 102 in combination with bevacizumab or motesanib in patients with advanced solid tumors. Clin. Cancer Res. 16, 2677–2687 (2010).

    CAS  Google Scholar 

  113. 113

    Schoffski, P. et al. A phase II study of the efficacy and safety of AMG 102 in patients with metastatic renal cell carcinoma. BJU Int. 108, 679–686 (2011).

    CAS  Google Scholar 

  114. 114

    Ryan, C. J. et al. Targeted MET inhibition in castration-resistant prostate cancer: a randomized phase II study and biomarker analysis with rilotumumab plus mitoxantrone and prednisone. Clin. Cancer Res. 19, 215–224 (2013).

    CAS  Google Scholar 

  115. 115

    Jones, S. F. et al. Safety, tolerability, and pharmacokinetics of TAK-701, a humanized anti-hepatocyte growth factor (HGF) monoclonal antibody, in patients with advanced nonhematologic malignancies: first-in-human phase I dose-escalation study [abstract]. J. Clin. Oncol. 28 (Suppl.), 3081 (2010).

    Google Scholar 

  116. 116

    Tabernero, J. et al. A pharmacodynamic/pharmacokinetic study of ficlatuzumab in patients with advanced solid tumors and liver metastases. Clin. Cancer Res. 20, 2793–2804 (2014).

    CAS  Google Scholar 

  117. 117

    Merchant, M. et al. Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent. Proc. Natl Acad. Sci. USA 110, E2987–E2996 (2013).

    CAS  Google Scholar 

  118. 118

    Spigel, D. R. et al. Randomized phase II trial of onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J. Clin. Oncol. 31, 4105–4114 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Spigel, D. R. et al. Onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIb or IV NSCLC: results from the pivotal phase III randomized, multicenter, placebo-controlled METLung (OAM4971g) global trial [abstract]. J. Clin. Oncol. 32 (Suppl.), 8000 (2014).

    Google Scholar 

  120. 120

    Petrelli, A. et al. Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity. Proc. Natl Acad. Sci. USA 103, 5090–5095 (2006).

    CAS  Google Scholar 

  121. 121

    Schelter, F. et al. A disintegrin and metalloproteinase-10 (ADAM-10) mediates DN30 antibody-induced shedding of the met surface receptor. J. Biol. Chem. 285, 26335–26340 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Wang, J. et al. Anti-c-Met monoclonal antibody ABT-700 breaks oncogene addiction in tumors with MET amplification. BMC Cancer 16, 105 (2016).

    PubMed  PubMed Central  Google Scholar 

  123. 123

    Smith, M. R. et al. Cabozantinib in chemotherapy-pretreated metastatic castration-resistant prostate cancer: results of a phase II nonrandomized expansion study. J. Clin. Oncol. 32, 3391–3399 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Choueiri, T. K. et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1814–1823 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Eder, J. P., Vande Woude, G. F., Boerner, S. A. & LoRusso, P. M. Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin. Cancer Res. 15, 2207–2214 (2009).

    CAS  Google Scholar 

  126. 126

    Eathiraj, S. et al. Discovery of a novel mode of protein kinase inhibition characterized by the mechanism of inhibition of human mesenchymal-epithelial transition factor (c-Met) protein autophosphorylation by ARQ 197. J. Biol. Chem. 286, 20666–20676 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    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).

    CAS  Google Scholar 

  128. 128

    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).

    CAS  Google Scholar 

  129. 129

    Malka, D. et al. FOLFOX alone or combined to rilotumumab or panitumumab as first-line treatment in patients (pts) with advanced gastroesophageal adenocarcinoma (AGEA): An open-label, randomized phase II trial (PRODIGE 17 ACCORD 20 MEGA) [abstract]. J. Clin. Oncol. 33 (Suppl.), 4013 (2015).

    Google Scholar 

  130. 130

    Van Cutsem, E. et al. Randomized phase Ib/II trial of rilotumumab or ganitumab with panitumumab versus panitumumab alone in patients with wild-type KRAS metastatic colorectal cancer. Clin. Cancer Res. 20, 4240–4250 (2014).

    CAS  Google Scholar 

  131. 131

    Shah, M. A. et al. Randomized phase II study of FOLFOX+/− MET inhibitor, onartuzumab (O), in advanced gastroesophageal adenocarcinoma (GEC) [abstract]. J. Clin. Oncol. 33 (Suppl. 3), 2 (2015).

    Google Scholar 

  132. 132

    Kang, Y. et al. Phase 1, open-label, dose-escalation, and expansion study of ABT-700, an anti-C-met antibody, in patients (pts) with advanced solid tumors [abstract]. J. Clin. Oncol. 33 (Suppl. 3), 167 (2015).

    Google Scholar 

  133. 133

    Bendell, J. C. et al. A randomized, double-blind, phase II study of first-line FOLFOX plus bevacizumab with onartuzumab versus placebo in patients with metastatic colorectal cancer (mCRC) [abstract]. J. Clin. Oncol. 33 (Suppl. 3), 663 (2015).

    Google Scholar 

  134. 134

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01472016 (2017).

  135. 135

    Kwak, E. et al. Clinical activity of AMG 337, an oral MET kinase inhibitor, in adult patients (pts) with MET-amplified gastroesophageal junction (GEJ), gastric (G), or esophageal (E) cancer [abstract]. J. Clin. Oncol. 33 (Suppl. 3), 1 (2015).

    Google Scholar 

  136. 136

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02344810 (2015).

  137. 137

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02205398 (2017).

  138. 138

    Jhawer, M. et al. Assessment of two dosing schedules of GSK1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in metastatic gastric cancer (GC): Interim results of a multicenter phase II study [abstract]. J. Clin. Oncol. 27 (Suppl.), 4502 (2009).

    Google Scholar 

  139. 139

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02435108 (2017).

  140. 140

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02008383 (2016).

  141. 141

    Eng, C. et al. A randomized, placebo-controlled, phase 1/2 study of tivantinib (ARQ 197) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild-type KRAS who have received first-line systemic therapy. Int. J. Cancer 139, 177–186 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Rimassa, L. et al. Phase II study of tivantinib (ARQ 197) in combination with cetuximab in EGFR inhibitor-resistant, MET-high, KRAS wild-type (KRASwt) metastatic colorectal cancer (mCRC) [abstract]. Ann. Oncol. 26 (Suppl. 4), 108–116 (2015).

    Google Scholar 

  143. 143

    Dziadziuszko, R. et al. Correlation between MET gene copy number by silver in situ hybridization and protein expression by immunohistochemistry in non-small cell lung cancer. J. Thorac. Oncol. 7, 340–347 (2012).

    PubMed  PubMed Central  Google Scholar 

  144. 144

    Wang, F. et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J. Mol. Diagn. 14, 22–29 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Choi, J. et al. Analysis of MET mRNA expression in gastric cancers using RNA in situ hybridization assay: its clinical implication and comparison with immunohistochemistry and silver in situ hybridization. PLoS ONE 9, e111658 (2014).

    PubMed  PubMed Central  Google Scholar 

  146. 146

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

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

    PubMed  PubMed Central  Google Scholar 

  148. 148

    Cappuzzo, F. et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J. Natl Cancer Inst. 97, 643–655 (2005).

    CAS  Google Scholar 

  149. 149

    Wolff, A. C. et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J. Clin. Oncol. 25, 118–145 (2007).

    CAS  Google Scholar 

  150. 150

    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).

    Google Scholar 

  151. 151

    Sadanandam, A. et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat. Med. 19, 619–625 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Qi, J. et al. Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors. Cancer Res. 71, 1081–1091 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

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

    CAS  Google Scholar 

  154. 154

    Petti, C. et al. Truncated RAF kinases drive resistance to MET inhibition in MET-addicted cancer cells. Oncotarget 6, 221–233 (2015).

    Google Scholar 

  155. 155

    Bachleitner-Hofmann, T. et al. HER kinase activation confers resistance to MET tyrosine kinase inhibition in MET oncogene-addicted gastric cancer cells. Mol. Cancer Ther. 7, 3499–3508 (2008).

    CAS  Google Scholar 

  156. 156

    Kim, D. C. et al. Resistance to the c-Met inhibitor KRC-108 induces the epithelial transition of gastric cancer cells. Oncol. Lett. 11, 991–997 (2016).

    CAS  Google Scholar 

  157. 157

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

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by MErCuRIC, funded by the European Commission's Framework Programme 7, under contract #602901.

Author information

Affiliations

Authors

Consortia

Contributions

All authors made a substantial contribution to all aspects of the preparation of this manuscript.

Corresponding author

Correspondence to Sandra Van Schaeybroeck.

Ethics declarations

Competing interests

P.L.P. has received honoraria from Amgen, Astrazeneca Boerhinger–Ingelheim, Integragen, Merck–Serono, Roche and Sanofi. J.T. has served on the advisory boards of Amgen, Bayer, Boehringer–Ingelheim, Celgene, Chugai, Lilly, MSD, Merck–Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho, and Takeda. P.G.J. is the founder and holds shares in Almac diagnostics, Fusion and CV6 Therapeutics, and has served as an expert adviser/consultant of Pfizer and Chugai Pharmaceuticals. The other authors declare no competing interests.

Supplementary information

Supplementary information S1 (table)

HGF and cMET inhibitors currently in preclinical development. (DOC 43 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bradley, C., Salto-Tellez, M., Laurent-Puig, P. et al. Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges. Nat Rev Clin Oncol 14, 562–576 (2017). https://doi.org/10.1038/nrclinonc.2017.40

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing