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:

Targeting MET in cancer: rationale and progress

A Corrigendum to this article was published on 17 August 2012

This article has been updated

Key Points

  • The growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor tyrosine kinase MET, the product of the MET proto-oncogene, provide essential signals for survival and long-distance migration of epithelial and myogenic precursor cells during embryogenesis. Cancer cells hijack HGF/SF–MET for invasion and metastasis, hence these molecules have emerged as key targets for cancer therapy.

  • Aberrant MET activation occurs in many types of cancer, and results from multiple mechanisms. Many carcinomas overexpress MET and the surrounding stroma overexpresses HGF/SF. Furthermore, certain patients with renal papillary, hepatocellular or gastric carcinomas carry point mutations in MET. These mutations have proved important in demonstrating a causal role of aberrant MET signalling in human cancer.

  • The intracellular signalling cascades activated by MET include the PI3K–AKT, RAC1–cell division control protein 42 (CDC42), RAP1 and RAS–MAPK pathways. An intricate network of cross-signalling involving the MET–epidermal growth factor receptor (EGFR), MET–vascular endothelial growth factor receptor (VEGFR) and MET–WNT pathways has also emerged in the past few years. This signalling network has major implications for therapy.

  • Structural studies of HGF/SF, the MET ectodomain and the pathways involved in activation of the precursor form of HGF/SF (pro-HGF/SF) have yielded important results and new opportunities for therapeutic intervention, namely specific inhibitors of the major HGF/SF activators, HGF/SF fragments with antagonistic activity — such as NK4 — and HGF/SF and MET antibodies.

  • Parallel efforts in the structural analysis of the MET kinase have led to extensive progress in the development of MET kinase inhibitors for cancer therapy, and three major classes of inhibitors have emerged from this work that differ in their binding mode, activity on MET kinase mutants and enzyme specificity.

  • A number of recent clinical trials have demonstrated strong activity of MET inhibitors in patients with a variety of advanced or metastatic tumours, including non-small-cell lung cancer (NSCLC), and breast, prostate, liver and renal cancer. MET inhibitors have also displayed clinical benefits in patients with NSCLC and patients with breast cancer who had developed resistance to EGFR therapy. These recent data clearly indicate that HGF/SF–MET therapeutics may have potential in several groups of cancer patients either alone or in combination with inhibitors of other signalling pathways.

Abstract

Uncontrolled cell survival, growth, angiogenesis and metastasis are essential hallmarks of cancer. Genetic and biochemical data have demonstrated that the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, the tyrosine kinase MET, have a causal role in all of these processes, thus providing a strong rationale for targeting these molecules in cancer. Parallel progress in understanding the structure and function of HGF/SF, MET and associated signalling components has led to the successful development of blocking antibodies and a large number of small-molecule MET kinase inhibitors. In this Review, we discuss these advances, as well as results from recent clinical studies that demonstrate that inhibiting MET signalling in several types of solid human tumours has major therapeutic value.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: The multidomain structure of MET and HGF/SF.
Figure 2: Signalling pathways activated by HGF/SF and MET.
Figure 3: Cooperation between the HGF and WNT–β-catenin pathways.
Figure 4: Extracellular inhibitors of HGF/SF and MET.
Figure 5: MET kinase inhibitors.
Figure 6: Clinical trials with HGF/SF–MET inhibitors.

Similar content being viewed by others

Change history

  • 17 August 2012

    In the legend to Figure 6c, the distribution according to therapeutic strategy (monotherapy versus combined therapy) involving HGF/SF–MET monotherapies should have read 44%.

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Park, M. et al. Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proc. Natl Acad. Sci. USA 84, 6379–6383 (1987). References 1 and 2 report a new transforming gene ( MET ) from a human osteogenic sarcoma cell line treated with N -methyl-N′-nitronitrosoguanidine. Subsequent work established that it is the fusion of regulatory sequences from chromosome 1 ( TPR ) and sequences from chromosome 7 encoding a receptor tyrosine kinase (MET).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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). Reference 3 shows that cells made autocrine for HGF/SF–MET expression become highly metastatic in immunocompromised mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Miyazawa, K. et al. Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. Biochem. Biophys. Res. Commun. 163, 967–973 (1989).

    Article  CAS  PubMed  Google Scholar 

  5. Nakamura, T., Nawa, K., Ichihara, A., Kaise, N. & Nishino, T. Purification and subunit structure of hepatocyte growth factor from rat platelets. FEBS Lett. 224, 311–316 (1987).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Zarnegar, R. & Michalopoulos, G. Purification and biological characterization of human hepatopoietin A, a polypeptide growth factor for hepatocytes. Cancer Res. 49, 3314–3320 (1989). References 4–7 describe the isolation, cloning and sequencing of a potent mitogen for rat hepatocyte cultures (HGF). Reference 6 further describes the sequence similarity between HGF and plasminogen.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Gherardi, E., Gray, J., Stoker, M., Perryman, M. & Furlong, R. Purification of scatter factor, a fibroblast-derived basic protein that modulates epithelial interactions and movement. Proc. Natl Acad. Sci. USA 86, 5844–5848 (1989). References 8 and 9 describe the discovery and characterization of a fibroblast-derived protein that causes dispersion of epithelial colonies (scatter factor). The reports establish a paracrine mechanism of action and describe changes in epithelial cells in culture that have now become known as EMT.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gherardi, E. & Stoker, M. Hepatocytes and scatter factor. Nature 346, 228 (1990).

    Article  CAS  PubMed  Google Scholar 

  11. Weidner, K. M. et al. Evidence for the identity of human scatter factor and human hepatocyte growth factor. Proc. Natl Acad. Sci. USA 88, 7001–7005 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). A molecular biological and biochemical study establishes that MET is the receptor for HGF/SF.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Uehara, Y. et al. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature 373, 702–705 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Bladt, F., Riethmacher, D., Isenmann, S., Aguzzi, A. & Birchmeier, C. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature 376, 768–771 (1995). References 13–15 define the roles of HGF/SF and MET in mouse development through genetic experiments. References 13 and 14 demonstrate roles in survival and differentiation of epithelial cells of the liver and placenta. Reference 15 reports that MET is essential for EMT of the ventral dermomyotome and migration of myogenic precursor cells into the limbs, tongue and other organs.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. 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). This report characterizes GAB1 as a universal docking protein of MET.

    Article  CAS  PubMed  Google Scholar 

  18. Lai, A. Z., Abella, J. V. & Park, M. Crosstalk in Met receptor oncogenesis. Trends Cell Biol. 19, 542–551 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Schmidt, L. et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nature Genet. 16, 68–73 (1997). This is the first report of missense mutations in MET in patients with hereditary papillary renal carcinoma and in certain non-familial forms of renal cancer.

    Article  CAS  PubMed  Google Scholar 

  21. Schiering, N. et al. Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met and its complex with the microbial alkaloid K-252a. Proc. Natl Acad. Sci. USA 100, 12654–12659 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gherardi, E. et al. Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc. Natl Acad. Sci. USA 103, 4046–4051 (2006). Reference 21 describes the first crystal structures of the kinase domain of MET. The report describes both the apo structure, as well as the structure of the kinase domain in complex with the inhibitor K-252A. Reference 22 describes Cryo-EM and SAXS structures of HGF/SF–MET complexes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kirchhofer, D. et al. Structural and functional basis of the serine protease-like hepatocyte growth factor β-chain in Met binding and signaling. J. Biol. Chem. 279, 39915–39924 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Owen, K. A. et al. Pericellular activation of hepatocyte growth factor by the transmembrane serine proteases matriptase and hepsin, but not by the membrane-associated protease uPA. Biochem. J. 426, 219–228 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Shimomura, T. et al. Activation of the zymogen of hepatocyte growth factor activator by thrombin. J. Biol. Chem. 268, 22927–22932 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Shimomura, T. et al. Hepatocyte growth factor activator inhibitor, a novel Kunitz-type serine protease inhibitor. J. Biol. Chem. 272, 6370–6376 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Kawaguchi, T. et al. Purification and cloning of hepatocyte growth factor activator inhibitor type 2, a Kunitz-type serine protease inhibitor. J. Biol. Chem. 272, 27558–27564 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. List, K. et al. Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation. Genes Dev. 19, 1934–1950 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Klezovitch, O. et al. Hepsin promotes prostate cancer progression and metastasis. Cancer Cell 6, 185–195 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Morris, M. R. et al. Tumor suppressor activity and epigenetic inactivation of hepatocyte growth factor activator inhibitor type 2/SPINT2 in papillary and clear cell renal cell carcinoma. Cancer Res. 65, 4598–4606 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Chirgadze, D. Y. et al. Crystal structure of the NK1 fragment of HGF/SF suggests a novel mode for growth factor dimerization and receptor binding. Nature Struct. Biol. 6, 72–79 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Ultsch, M., Lokker, N. A., Godowski, P. J. & de Vos, A. M. Crystal structure of the NK1 fragment of human hepatocyte growth factor at 2.0 A resolution. Structure 6, 1383–1393 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Tolbert, W. D., Daugherty-Holtrop, J., Gherardi, E., Vande Woude, G. & Xu, H. E. Structural basis for agonism and antagonism of hepatocyte growth factor. Proc. Natl Acad. Sci. USA 107, 13264–13269 (2010). References 31 and 32 are the first reports of the crystal structure of the NK1 fragment of HGF/SF. An identical head-to-tail dimer is described in two different crystal forms. Reference 33 provides the first crystal structure of NK2, the product of the major HGF/SF splice variant.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Niemann, H. H. et al. Structure of the human receptor tyrosine kinase met in complex with the listeria invasion protein InlB. Cell 130, 235–246 (2007). References 34 and 35 report on the first two crystal structures of fragments of the MET ectodomain in complex with the SPH domain of HGF/SF (reference 34) or the bacterial protein InlB (reference 35).

    Article  CAS  PubMed  Google Scholar 

  36. Ferraris, D. M., Gherardi, E., Di, Y., Heinz, D. W. & Niemann, H. H. Ligand-mediated dimerization of the Met receptor tyrosine kinase by the bacterial invasion protein InlB. J. Mol. Biol. 395, 522–532 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. 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). This report describes the bidentate docking site of MET (Y1349 and Y1356), which is essential in MET signalling and binds various adaptor molecules.

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Paliouras, G. N., Naujokas, M. A. & Park, M. Pak4, a novel Gab1 binding partner, modulates cell migration and invasion by the Met receptor. Mol. Cell. Biol. 29, 3018–3032 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Schaeper, U. et al. Distinct requirements for Gab1 in Met and EGF receptor signaling in vivo. Proc. Natl Acad. Sci. USA 104, 15376–15381 (2007). References 40 and 41 describe the involvement of the tyrosine phosphatase SHP2 in downstream signalling of MET.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Grossmann, K. S., Rosario, M., Birchmeier, C. & Birchmeier, W. The tyrosine phosphatase Shp2 in development and cancer. Adv. Cancer Res. 106, 53–89 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Ishibe, S. et al. Met and the epidermal growth factor receptor act cooperatively to regulate final nephron number and maintain collecting duct morphology. Development 136, 337–345 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Montesano, R., Matsumoto, K., Nakamura, T. & Orci, L. Identification of a fibroblast-derived epithelial morphogen as hepatocyte growth factor. Cell 67, 901–908 (1991).

    Article  CAS  PubMed  Google Scholar 

  45. Woolf, A. S. et al. Roles of hepatocyte growth factor/scatter factor and the met receptor in the early development of the metanephros. J. Cell Biol. 128, 171–184 (1995).

    Article  CAS  PubMed  Google Scholar 

  46. Mosesson, Y., Mills, G. B. & Yarden, Y. Derailed endocytosis: an emerging feature of cancer. Nature Rev. Cancer 8, 835–850 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Joffre, C. et al. A direct role for Met endocytosis in tumorigenesis. Nature Cell Biol. 13, 827–837 (2011). This report describes binding of the E3-ubiquitin ligase CBL to the juxtamembrane region of MET leading to downregulation of the receptor.

    Article  CAS  PubMed  Google Scholar 

  48. 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).

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  51. Abella, J. V. et al. Met/Hepatocyte growth factor receptor ubiquitination suppresses transformation and is required for Hrs phosphorylation. Mol. Cell. Biol. 25, 9632–9645 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  53. Asaoka, Y. et al. Gastric cancer cell line Hs746T harbors a splice site mutation of c-Met causing juxtamembrane domain deletion. Biochem. Biophys. Res. Commun. 394, 1042–1046 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Dietrich, S. et al. The role of SF/HGF and c-Met in the development of skeletal muscle. Development 126, 1621–1629 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    Article  CAS  PubMed  Google Scholar 

  57. Michalopoulos, G. K. & DeFrances, M. C. Liver regeneration. Science 276, 60–66 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Huh, C. G. et al. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc. Natl Acad. Sci. USA 101, 4477–4482 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G. & Birchmeier, W. β-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105, 533–545 (2001). References 56, 57 and 60 describe an essential role of MET in liver regeneration and skin wound healing.

    Article  CAS  PubMed  Google Scholar 

  61. Snippert, H. J. et al. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science 327, 1385–1389 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Nakamura, T., Mizuno, S., Matsumoto, K., Sawa, Y. & Matsuda, H. Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF. J. Clin. Invest. 106, 1511–1519 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ma, P. C. et al. Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer 47, 1025–1037 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Graveel, C. et al. Activating Met mutations produce unique tumor profiles in mice with selective duplication of the mutant allele. Proc. Natl Acad. Sci. USA 101, 17198–17203 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ponzo, M. G. et al. Met induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer. Proc. Natl Acad. Sci. USA 106, 12903–12908 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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).

    Article  CAS  PubMed  Google Scholar 

  68. Houldsworth, J., Cordon-Cardo, C., Ladanyi, M., Kelsen, D. P. & Chaganti, R. S. Gene amplification in gastric and esophageal adenocarcinomas. Cancer Res. 50, 6417–6422 (1990).

    CAS  PubMed  Google Scholar 

  69. Kuniyasu, H. et al. Frequent amplification of the c-met gene in scirrhous type stomach cancer. Biochem. Biophys. Res. Commun. 189, 227–232 (1992).

    Article  CAS  PubMed  Google Scholar 

  70. Rege-Cambrin, G. et al. Karyotypic analysis of gastric carcinoma cell lines carrying an amplified c-met oncogene. Cancer Genet. Cytogenet. 64, 170–173 (1992).

    Article  CAS  PubMed  Google Scholar 

  71. Knudsen, B. S. & Vande Woude, G. Showering c-MET-dependent cancers with drugs. Curr. Opin. Genet. Dev. 18, 87–96 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yamamoto, N., Mammadova, G., Song, R. X., Fukami, Y. & Sato, K. Tyrosine phosphorylation of p145met mediated by EGFR and Src is required for serum-independent survival of human bladder carcinoma cells. J. Cell Sci. 119, 4623–4633 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007). The first report that cancer cells from patients with NSCLC acquire resistance to EGFR inhibitors through MET and ERBB3 signalling, and that combinations of EGFR and MET inhibitors can restore the suppression of cell growth.

    Article  CAS  PubMed  Google Scholar 

  76. Turke, A. B. et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17, 77–88 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhang, Y. W. et al. MET kinase inhibitor SGX523 synergizes with epidermal growth factor receptor inhibitor erlotinib in a hepatocyte growth factor-dependent fashion to suppress carcinoma growth. Cancer Res. 70, 6880–6890 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  79. Swiercz, J. M., Worzfeld, T. & Offermanns, S. Semaphorin 4D signaling requires the recruitment of phospholipase C γ into the plexin-B1 receptor complex. Mol. Cell. Biol. 29, 6321–6334 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Klaus, A. & Birchmeier, W. Wnt signalling and its impact on development and cancer. Nature Rev. Cancer 8, 387–398 (2008).

    Article  CAS  Google Scholar 

  81. Boon, E. M., van der Neut, R., van de Wetering, M., Clevers, H. & Pals, S. T. Wnt signaling regulates expression of the receptor tyrosine kinase met in colorectal cancer. Cancer Res. 62, 5126–5128 (2002).

    CAS  PubMed  Google Scholar 

  82. Liu, Y. et al. Coordinate integrin and c-Met signaling regulate Wnt gene expression during epithelial morphogenesis. Development 136, 843–853 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Monga, S. P. et al. Hepatocyte growth factor induces Wnt-independent nuclear translocation of β-catenin after Met-β-catenin dissociation in hepatocytes. Cancer Res. 62, 2064–2071 (2002).

    CAS  PubMed  Google Scholar 

  84. Brembeck, F. H. et al. Essential role of BCL9–2 in the switch between β-catenin's adhesive and transcriptional functions. Genes Dev. 18, 2225–2230 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Bhowmick, N. A. et al. TGF-β signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303, 848–851 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Sridhar, S. C. & Miranti, C. K. Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases. Oncogene 25, 2367–2378 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Takahashi, M., Sugiura, T., Abe, M., Ishii, K. & Shirasuna, K. Regulation of c-Met signaling by the tetraspanin KAI-1/CD82 affects cancer cell migration. Int. J. Cancer 121, 1919–1929 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Sharp, R. et al. Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis. Nature Med. 8, 1276–1280 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Abounader, R. & Laterra, J. Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis. Neuro Oncol. 7, 436–451 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Bussolino, F. et al. Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J. Cell Biol. 119, 629–641 (1992).

    Article  CAS  PubMed  Google Scholar 

  91. Grant, D. S. et al. Scatter factor induces blood vessel formation in vivo. Proc. Natl Acad. Sci. USA 90, 1937–1941 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhang, Y. W., Su, Y., Volpert, O. V. & Vande Woude, G. F. Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation. Proc. Natl Acad. Sci. USA 100, 12718–12723 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sulpice, E. et al. Cross-talk between the VEGF-A and HGF signalling pathways in endothelial cells. Biol. Cell 101, 525–539 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Puri, N. et al. A selective small molecule inhibitor of c-Met, PHA665752, inhibits tumorigenicity and angiogenesis in mouse lung cancer xenografts. Cancer Res. 67, 3529–3534 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Cantelmo, A. R. et al. Cell delivery of Met docking site peptides inhibit angiogenesis and vascular tumor growth. Oncogene 29, 5286–5298 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Hara, S. et al. Hypoxia enhances c-Met/HGF receptor expression and signaling by activating HIF-1α in human salivary gland cancer cells. Oral Oncol. 42, 593–598 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Ide, T. et al. Tumor-stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c-Met pathway. Int. J. Cancer 119, 2750–2759 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. Pennacchietti, S. et al. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3, 347–361 (2003). This report shows that hypoxia controls MET expression in carcinoma and sarcoma cells, a finding with important consequences for therapy.

    Article  PubMed  Google Scholar 

  99. Scarpino, S. et al. 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. 202, 352–358 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Qian, F. et al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res. 69, 8009–8016 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Nakagawa, T. et al. E7050: a dual c-Met and VEGFR-2 tyrosine kinase inhibitor promotes tumor regression and prolongs survival in mouse xenograft models. Cancer Sci. 101, 210–215 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. You, W. K. & McDonald, D. M. The hepatocyte growth factor/c-Met signaling pathway as a therapeutic target to inhibit angiogenesis. BMB Rep. 41, 833–839 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  104. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Muschel, R. J., Williams, J. E., Lowy, D. R. & Liotta, L. A. Harvey ras induction of metastatic potential depends upon oncogene activation and the type of recipient cell. Am. J. Pathol. 121, 1–8 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Webb, C. P. et al. Evidence for a role of Met-HGF/SF during Ras-mediated tumorigenesis/metastasis. Oncogene 17, 2019–2025 (1998).

    Article  CAS  PubMed  Google Scholar 

  110. Ridley, A. J., Comoglio, P. M. & Hall, A. Regulation of scatter factor/hepatocyte growth factor responses by Ras, Rac, and Rho in MDCK cells. Mol. Cell. Biol. 15, 1110–1122 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nature Cell Biol. 12, 468–476 (2010). A report describing stromal HGF/SF as a mesenchymal niche factor that cooperates with epithelial MET and WNT–β-catenin signalling in the maintenance of colon cancer stem cells.

    Article  CAS  PubMed  Google Scholar 

  112. Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med. 3, 730–737 (1997).

    Article  CAS  PubMed  Google Scholar 

  113. Kelly, P. N., Dakic, A., Adams, J. M., Nutt, S. L. & Strasser, A. Tumor growth need not be driven by rare cancer stem cells. Science 317, 337 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Clevers, H. Wnt/β-catenin signaling in development and disease. Cell 127, 469–480 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Malanchi, I. et al. Cutaneous cancer stem cell maintenance is dependent on β-catenin signalling. Nature 452, 650–653 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Piccirillo, S. G. et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444, 761–765 (2006).

    Article  CAS  PubMed  Google Scholar 

  117. Wend, P., Holland, J. D., Ziebold, U. & Birchmeier, W. Wnt signaling in stem and cancer stem cells. Semin. Cell Dev. Biol. 21, 855–863 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Neuss, S., Becher, E., Woltje, M., Tietze, L. & Jahnen-Dechent, W. Functional expression of HGF and HGF receptor/c-met in adult human mesenchymal stem cells suggests a role in cell mobilization, tissue repair, and wound healing. Stem Cells 22, 405–414 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Son, B. R. et al. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells 24, 1254–1264 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Tesio, M. et al. Enhanced c-Met activity promotes G.-CSF-induced mobilization of hematopoietic progenitor cells via ROS signaling. Blood 117, 419–428.

  121. Urbanek, K. et al. Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival. Circ. Res. 97, 663–673 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Tatsumi, R., Anderson, J. E., Nevoret, C. J., Halevy, O. & Allen, R. E. HGF/SF is present in normal adult skeletal muscle and is capable of activating satellite cells. Dev. Biol. 194, 114–128 (1998).

    Article  CAS  PubMed  Google Scholar 

  123. Kamiya, A., Gonzalez, F. J. & Nakauchi, H. Identification and differentiation of hepatic stem cells during liver development. Front. Biosci. 11, 1302–1310 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Suzuki, A., Nakauchi, H. & Taniguchi, H. Prospective isolation of multipotent pancreatic progenitors using flow-cytometric cell sorting. Diabetes 53, 2143–2152 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).

    Article  CAS  PubMed  Google Scholar 

  126. Previdi, S. et al. Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and β-catenin/Wnt pathways. Eur. J. Cancer 46, 1679–1691 (2010).

    Article  CAS  PubMed  Google Scholar 

  127. Masuya, D. et al. The tumour-stromal interaction between intratumoral c-Met and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer patients. Br. J. Cancer 90, 1555–1562 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Mahtouk, K., Tjin, E. P., Spaargaren, M. & Pals, S. T. The HGF/MET pathway as target for the treatment of multiple myeloma and B-cell lymphomas. Biochim. Biophys. Acta 1806, 208–219 (2010).

    CAS  PubMed  Google Scholar 

  129. Sukhdeo, K. et al. Targeting the β-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc. Natl Acad. Sci. USA 104, 7516–7521 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Shia, S. et al. Conformational lability in serine protease active sites: structures of Hepatocyte Growth Factor Activator (HGFA) alone and with the inhibitory domain from HGFA inhibitor-1B. J. Mol. Biol. 346, 1335–1349 (2005).

    Article  CAS  PubMed  Google Scholar 

  131. Li, W. et al. Pegylated kunitz domain inhibitor suppresses hepsin-mediated invasive tumor growth and metastasis. Cancer Res. 69, 8395–8402 (2009).

    Article  CAS  PubMed  Google Scholar 

  132. Wu, Y. et al. Structural insight into distinct mechanisms of protease inhibition by antibodies. Proc. Natl Acad. Sci. USA 104, 19784–19789 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ganesan, R. et al. Unraveling the allosteric mechanism of serine protease inhibition by an antibody. Structure 17, 1614–1624 (2009).

    Article  CAS  PubMed  Google Scholar 

  134. Farady, C. J., Sun, J., Darragh, M. R., Miller, S. M. & Craik, C. S. The mechanism of inhibition of antibody-based inhibitors of membrane-type serine protease 1 (MT-SP1). J. Mol. Biol. 369, 1041–1051 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Cao, B. et al. Neutralizing monoclonal antibodies to hepatocyte growth factor/scatter factor (HGF/SF) display antitumor activity in animal models. Proc. Natl Acad. Sci. USA 98, 7443–7448 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 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).

    Article  CAS  PubMed  Google Scholar 

  137. Jakubczak, J. L., LaRochelle, W. J. & Merlino, G. NK1, a natural splice variant of hepatocyte growth factor/scatter factor, is a partial agonist in vivo. Mol. Cell. Biol. 18, 1275–1283 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Tolbert, W. D. et al. A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist. Proc. Natl Acad. Sci. USA 104, 14592–14597 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Youles, M. et al. Engineering the NK1 fragment of hepatocyte growth factor/scatter factor as a MET receptor antagonist. J. Mol. Biol. 377, 616–622 (2008).

    Article  CAS  PubMed  Google Scholar 

  140. Otsuka, T. et al. Disassociation of met-mediated biological responses in vivo: the natural hepatocyte growth factor/scatter factor splice variant NK2 antagonizes growth but facilitates metastasis. Mol. Cell. Biol. 20, 2055–2065 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Date, K., Matsumoto, K., Shimura, H., Tanaka, M. & Nakamura, T. HGF/NK4 is a specific antagonist for pleiotrophic actions of hepatocyte growth factor. FEBS Lett. 420, 1–6 (1997).

    Article  CAS  PubMed  Google Scholar 

  142. Nakamura, T., Sakai, K. & Matsumoto, K. Anti-cancer approach with NK4: bivalent action and mechanisms. Anticancer Agents Med. Chem. 10, 36–46 (2010).

    Article  CAS  PubMed  Google Scholar 

  143. Kong-Beltran, M., Stamos, J. & Wickramasinghe, D. The Sema domain of Met is necessary for receptor dimerization and activation. Cancer Cell 6, 75–84 (2004).

    Article  CAS  PubMed  Google Scholar 

  144. Jin, H. et al. MetMAb, the one-armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival. Cancer Res. 68, 4360–4368 (2008).

    Article  CAS  PubMed  Google Scholar 

  145. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Pacchiana, G. et al. Monovalency unleashes the full therapeutic potential of the DN-30 anti-Met antibody. J. Biol. Chem. 285, 36149–36157 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Goetsch, L. Novel antibodies inhibitong c-met dimerization, and uses thereof (2007). http://ip.com/patapp/EP2188312A2.

  149. Underiner, T. L., Herbertz, T. & Miknyoczki, S. J. Discovery of small molecule c-Met inhibitors: evolution and profiles of clinical candidates. Anticancer Agents Med. Chem. 10, 2188317–2188327 (2010).

    Article  Google Scholar 

  150. Wang, W. et al. Structural characterization of autoinhibited c-Met kinase produced by coexpression in bacteria with phosphatase. Proc. Natl Acad. Sci. USA 103, 3563–3568 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Rickert, K. W. et al. Structural basis for selective small-molecule kinase inhibition of activated c-Met. J. Biol. Chem. 286, 11218–11225 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Buchanan, S. G. et al. SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo. Mol. Cancer Ther. 8, 3181–3190 (2009).

    Article  CAS  PubMed  Google Scholar 

  153. Timofeevski, S. L. et al. Enzymatic characterization of c-Met receptor tyrosine kinase oncogenic mutants and kinetic studies with aminopyridine and triazolopyrazine inhibitors. Biochemistry 48, 5339–5349 (2009).

    Article  CAS  PubMed  Google Scholar 

  154. Schroeder, G. M. et al. Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluor ophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J. Med. Chem. 52, 1251–1254 (2009).

    Article  CAS  PubMed  Google Scholar 

  155. D'Angelo, N. D. et al. Design, synthesis, and biological evaluation of potent c-Met inhibitors. J. Med. Chem. 51, 5766–5779 (2008).

    Article  CAS  PubMed  Google Scholar 

  156. Munshi, N. et al. ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol. Cancer Ther. 9, 1544–1553 (2010).

    Article  CAS  PubMed  Google Scholar 

  157. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Kwak, E. L. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. O'Brien, S. G. et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 348, 994–1004 (2003).

    Article  CAS  PubMed  Google Scholar 

  160. Knudsen, B. S. et al. A novel multipurpose monoclonal antibody for evaluating human c-Met expression in preclinical and clinical settings. Appl. Immunohistochem. Mol. Morphol. 17, 57–67 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Inoue, T. et al. Activation of c-Met (hepatocyte growth factor receptor) in human gastric cancer tissue. Cancer Sci. 95, 803–808 (2004).

    Article  CAS  PubMed  Google Scholar 

  162. Mueller, K. L., Hunter, L. A., Ethier, S. P. & Boerner, J. L. Met and c-Src cooperate to compensate for loss of epidermal growth factor receptor kinase activity in breast cancer cells. Cancer Res. 68, 3314–3322 (2008).

    Article  CAS  PubMed  Google Scholar 

  163. Zhang, Y., Guessous, F., Kofman, A., Schiff, D. & Abounader, R. XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC. IDrugs 13, 112–121 (2010).

    PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  165. Corso, S. et al. Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition. Mol. Cancer 9, 121 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Spigel DR. et al. Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. J. Clin. Oncol. Abstr. 29, 7505 (2011). References 166 and 167 are the first reports to demonstrate that combined treatment of subgroups of patients with NSCLC with EGFR and MET inhibitors increases progression-free survival and overall survival.

    Article  Google Scholar 

  168. Iveson, T. et al. Safety and efficacy of epirubicin, cisplatin, and capecitabine (ECX) plus rilotumumab (R) as first-line treatment for unresectable locally advanced (LA) or metastatic (M) gastric or esophagogastric junction (EGJ) adenocarcinoma. Proc. Eur. Multidisc. Cancer Congr. Abstr. 6.504 (Stockholm, 2011).

  169. Von Pawel J. et al. Final results from Arq 197–209: a global randomized placebo- controlled phase 2 clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGFR- inhibitor Naıve patients with advanced non-small cell lung cancer (NSCLC). J. Thoracic Oncol. Abstr. 5, 1 (2010).

    Article  Google Scholar 

  170. Bagai, R., Fan, W. & Ma, P. C. ARQ-197, an oral small-molecule inhibitor of c-Met for the treatment of solid tumors. IDrugs 13, 404–414 (2010).

    CAS  PubMed  Google Scholar 

  171. Gordon MS. et al. Activity of cabozantinib (XL184) in soft tissue and bone: results of a phase II randomized discontinuation trial (RDT) in patients (pts) with advanced solid tumors. J. Clin. Oncol. Abstr. 29, 3010 (2011).

    Article  Google Scholar 

  172. Buckanovich RJ. et al. Activity of cabozantinib (XL184) in advanced ovarian cancer patients (pts): results from a phase II randomized discontinuation trial (RDT). J. Clin. Oncol. Abstr. 29, 5008 (2011).

    Article  Google Scholar 

  173. Hussain M. et al. Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): results from a phase II randomized discontinuation trial. J. Clin. Oncol. 29, 4516 (2011).

    Article  Google Scholar 

  174. Kurzrock, R. et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J. Clin. Oncol. 29, 2660–2666 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Liu, L. et al. Synergistic effects of foretinib with HER-targeted agents in MET and HER1- or HER2-coactivated tumor cells. Mol. Cancer Ther. 10, 518–530 (2011).

    Article  CAS  PubMed  Google Scholar 

  176. Zhang, J. et al. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463, 501–506 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  178. 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). This report defines the domain structure of extracellular MET through deletion mutagenesis and computational studies. The report establishes that MET contains a 7-balded β-propeller similar to the one present in the integrin α-chain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. 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).

    Article  CAS  PubMed  Google Scholar 

  180. DeLano, W. L. The PyMOL Molecular Graphics System. (DeLano Scientific, 2002).

    Google Scholar 

  181. Weidner, K. M., Behrens, J., Vandekerckhove, J. & Birchmeier, W. Scatter factor: molecular characteristics and effect on the invasiveness of epithelial cells. J. Cell Biol. 111, 2097–2108 (1990). This report demonstrates the first time that HGF/SF induces invasion of human carcinoma cells into three-dimensional matrices (that is, induces the invasive phenotype).

    Article  CAS  PubMed  Google Scholar 

  182. Rong, S. et al. Tumorigenicity of the met proto-oncogene and the gene for hepatocyte growth factor. Mol. Cell. Biol. 12, 5152–5158 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Sakata, H. et al. Hepatocyte growth factor/scatter factor overexpression induces growth, abnormal development, and tumor formation in transgenic mouse livers. Cell Growth Differ. 7, 1513–1523 (1996).

    CAS  PubMed  Google Scholar 

  184. Itoh, M. et al. Role of Gab1 in heart, placenta, and skin development and growth factor- and cytokine-induced extracellular signal-regulated kinase mitogen-activated protein kinase activation. Mol. Cell. Biol. 20, 3695–3704 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Sachs, M. et al. Essential role of Gab1 for signaling by the c-Met receptor in vivo. J. Cell Biol. 150, 1375–1384 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Shen, Y., Naujokas, M., Park, M. & Ireton, K. InIB-dependent internalization of Listeria is mediated by the Met receptor tyrosine kinase. Cell 103, 501–510 (2000).

    Article  CAS  PubMed  Google Scholar 

  187. Stein, U. et al. MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nature Med. 15, 59–67 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge J. Heuberger (MDC Berlin) for initial drawing of figures 2 and 3 and H. Niemann (University of Bielefeld) for critical reading of the manuscript. E.G. and W.B. acknowledge funding under the SFMET Project of the EU FP7 Programme and the generosity of the Jay and Betty Van Andel Foundation.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Ermanno Gherardi, Walter Birchmeier, Carmen Birchmeier or George Vande Woude.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Glossary

Clastogenic carcinogen

A chemical agent that can cause cancer as a result of its ability to induce chromosome breaks, which results in the loss or rearrangement of parts of one or more chromosomes.

Coagulation cascade

An ordered sequence of chemical reactions triggered by tissue components after tissue damage and catalysed by enzymes present in serum that ultimately causes the formation of a blood clot.

Myogenic progenitor cells

Progenitor cells that have the potential to differentiate into skeletal muscle.

Epithelial dermomyotome

A transient epithelial structure of the embryo that will give rise to skeletal muscle, dermis and other cell types in later development.

Keratinocytes

Epithelial cells of the skin and its appendages, such as hair and skin glands.

Autocrine signalling

A type of cell signalling in which the same cell produces both the chemical messenger (a hormone, growth factor or cytokine) and the membrane receptor that triggers the biological response to the messenger.

π stacking interactions

A chemical interaction between aromatic rings that is commonly seen in DNA and RNA structures, nucleoprotein complexes and between complexes of small organic compounds with proteins. The interaction is mediated by π orbitals, and the two rings are piled (stacked).

Progression-free survival

(PFS). A statistical parameter that measures the time — for example, after diagnosis and/or treatment — in which the disease remains stable (progression free). It can also be expressed as the proportion of patients whose disease has remained stable after diagnosis and/or treatment at a specified time.

Overall survival

A statistical parameter that measures the survival time of a patient or a patient group after diagnosis and/or treatment, regardless of the cause of death. It can also be expressed as the proportion of patients who remain alive at a specified time.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gherardi, E., Birchmeier, W., Birchmeier, C. et al. Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12, 89–103 (2012). https://doi.org/10.1038/nrc3205

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3205

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer