Skip to main content
SpringerLink
Log in

Therapeutic Targeting of the Receptor Tyrosine Kinase Met

  • Chapter
Molecular Targeting and Signal Transduction

Part of the book series: Cancer Treatment and Research ((CTAR,volume 119))

Conclusion

There are different options to inhibit Met activation and these are in part limited depending on the transforming phenotype. For example, inhibiting ligand/receptor interactions may be a useful approach when inhibiting a paracrine/autocrine mechanism but will show little effect on a gain-of-function mutation of Met. It still remains unknown as to how much Met inhibition is required to achieve clinically beneficial anti-tumor and anti-metastatic results. The answer may potentially be different depending upon whether the ‘tumorigenic culprit’ lies with Met expression or mutations of the RTK. It will be necessary to further study and optimize targeted approaches for clinical studies. Another intriguing area of research, with specific Met inhibitors available, would be to test the drug efficaciesagainst different mutant forms of the Met oncoprotein. It is possible that some mutations of Met may cause resistance, or conversely a greater susceptibility, to the inhibitors. Among various strategies to inhibit HGF/Met signaling, developing specific small molecule inhibitors against Met may have the greatest potential in molecularly targeted anti-cancer therapy. However, lessons learned from Gleevec (imatinib mesylate) treatment in chronic myelogenous leukemia demonstrate that drug resistance is a real issu therapeutically. It will therefore be necessary to furthercharacterize the signaling mechanisms behind Met-mediated proliferation and other biological effects to identify additional molecules for targeted therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

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

    CAS  PubMed  Google Scholar 

  2. Park M, Dean M, Cooper CS, Schmidt M, O’Brien SJ, Blair DG, Vande Woude GF. Mechanism of met oncogene activation. Cell. 1986;45:895–904.

    Article  CAS  PubMed  Google Scholar 

  3. Tempest PR, Reeves BR, Spurr NK, Rance AJ, Chan AM, Brookes P. Activation of the met oncogene in the human MNNG-HOS cell line involves a chromosomal rearrangement. Carcinogenesis. 1986;7:2051–2057.

    CAS  PubMed  Google Scholar 

  4. Rodrigues GA, Park M. Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase. Mol Cell Biol. 1993;13:6711–6722.

    CAS  PubMed  Google Scholar 

  5. Zhen Z, Giordano S, Longati P, Medico E, Campiglio M, Comoglio PM. Structural and functional domains critical for constitutive activation of the HGF-receptor (Met). Oncogene. 1994;9:1691–1697.

    CAS  PubMed  Google Scholar 

  6. Gohda E, Tsubouchi H, Nakayama H, Hirono S, Takahashi K, Koura M, Hashimoto S, Daikuhara Y. Human hepatocyte growth factor in plasma from patients with fulminant hepatic failure. Exp Cell Res. 1986; 166:139–150.

    Article  CAS  PubMed  Google Scholar 

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

    Article  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. 1987;327:239–242.

    Article  CAS  PubMed  Google Scholar 

  9. Comoglio PM, Boccaccio C. The HGF receptor family: unconventional signal transducers for invasive cell growth. Genes Cells. 1996;l:347–354.

    Google Scholar 

  10. Maestrini E, Tamagnone L, Longati P, Cremona O, Gulisano M, Bione S, Tamanini F, Neel BG, Toniolo D, Comoglio PM. A family of transmembrane proteins with homology to the MET-hepatocyte growth factor receptor. Proc Natl Acad Sci U S A. 1996;93:674–678.

    Article  CAS  PubMed  Google Scholar 

  11. Duh FM, Scherer SW, Tsui LC, Lerman MI, Zbar B, Schmidt L. Gene structure of the human MET proto-oncogene. Oncogene. 1997;15:1583–1586.

    Article  CAS  PubMed  Google Scholar 

  12. Liu Y. The human hepatocyte growth factor receptor gene: complete structural organization and promoter characterization. Gene. 1998;215:159–169.

    Article  CAS  PubMed  Google Scholar 

  13. Kamada M, Komori A, Chiba S, Nakao T. A prospective study of congenital cytomegalovirus infection in Japan. Scand J Infect Dis. 1983;15:227–232.

    CAS  PubMed  Google Scholar 

  14. Rodrigues GA, Park M. Autophosphorylation modulates the kinase activity and oncogenic potential of the Met receptor tyrosine kinase. Oncogene. 1994;9:2019–2027.

    CAS  PubMed  Google Scholar 

  15. Petrelli A, Gilestro GF, Lanzardo S, Comoglio PM, Migone N, Giordano S. The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met. Nature. 2002;416:187–190.

    Article  CAS  PubMed  Google Scholar 

  16. Furge KA, Zhang YW, Vande Woude GF. Met receptor tyrosine kinase: enhanced signaling through adapter proteins. Oncogene. 2000;19:5582–5589.

    Article  CAS  PubMed  Google Scholar 

  17. Iwazawa T, Shiozaki H, Doki Y, Inoue M, Tamura S, Matsui S, Monden T, Matsumoto K, Nakamura T, Monden M. Primary human fibroblasts induce diverse tumor invasiveness: involvement of HGF as an important paracrine factor. Jpn J Cancer Res. 1996;87:1134–1142.

    CAS  PubMed  Google Scholar 

  18. Weimar IS, Miranda N, Muller EJ, Hekman A, Kerst JM, de Gast GC, Gerritsen WR. Hepatocyte growth factor/scatter factor (HGF/SF) is produced by human bone marrow stromal cells and promotes proliferation, adhesion and survival of human hematopoietic progenitor cells (CD34+). Exp Hematol. 1998;26:885–894.

    CAS  PubMed  Google Scholar 

  19. Nakashiro K, Okamoto M, Hayashi Y, Oyasu R. Hepatocyte growth factor secreted by prostate-derived stromal cells stimulates growth of androgen-independent human prostatic carcinoma cells. Am J Pathol. 2000;157:795–803.

    CAS  PubMed  Google Scholar 

  20. Takai K, Hara J, Matsumoto K, Hosoi G, Osugi Y, Tawa A, Okada S, Nakamura T. Hepatocyte growth factor is constitutively produced by human bone marrow stromal cells and indirectly promotes hematopoiesis. Blood. 1997;89:1560–1565.

    CAS  PubMed  Google Scholar 

  21. Soman NR, Correa P, Ruiz BA, Wogan GN. The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions. Proc Natl Acad Sci U S A. 1991;88:4892–4896.

    CAS  PubMed  Google Scholar 

  22. Yu J, Miehlke S, Ebert MP, Hoffmann J, Breidert M, Alpen B, Starzynska T, Stolte Prof M, Malfertheiner P, Bayerdorffer E. Frequency of TPR-MET rearrangement in patients with gastric carcinoma and in first-degree relatives. Cancer. 2000;88:1801–1806.

    CAS  PubMed  Google Scholar 

  23. Heideman DA, Snijders PJ, Bloemena E, Meijer CJ, Offerhaus GJ, Meuwissen SG, Gerritsen WR, Craanen ME. Absence of tpr-met and expression of c-met in human gastric mucosa and carcinoma. J Pathol. 2001;194:428–435.

    Article  CAS  PubMed  Google Scholar 

  24. Natali PG, Prat M, Nicotra MR, Bigotti A, Olivero M, Comoglio PM, Di Renzo MF. Overexpression of the met/HGF receptor in renal cell carcinomas. Int J Cancer. 1996;69:212–217.

    Article  CAS  PubMed  Google Scholar 

  25. Olivero M, Rizzo M, Madeddu R, Casadio C, Pennacchietti S, Nicotra MR, Prat M, Maggi G, Arena N, Natali PG, Comoglio PM, Di Renzo MF. Overexpression and activation of hepatocyte growth factor/scatter factor in human non-small-cell lung carcinomas. Br J Cancer. 1996;74:1862–1868.

    CAS  PubMed  Google Scholar 

  26. Porte H, Triboulet JP, Kotelevets L, Carrat F, Prevot S, Nordlinger B, DiGioia Y, Wurtz A, Comoglio P, Gespach C, Chastre E. Overexpression of stromelysin-3, BM-40/SPARC, and MET genes in human esophageal carcinoma: implications for prognosis. Clin Cancer Res. 1998;4:1375–1382.

    CAS  PubMed  Google Scholar 

  27. Maulik G, Kijima T, Ma PC, Ghosh SK, Lin J, Shapiro GI, Schaefer E, Tibaldi E, Johnson BE, Salgia R. Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer. Clin Cancer Res. 2002;8:620–627.

    CAS  PubMed  Google Scholar 

  28. Ramirez R, Hsu D, Patel A, Fenton C, Dinauer C, Tuttle RM, Francis GL. Over-expression of hepatocyte growth factor/scatter factor (HGF/SF) and the HGF/SF receptor (cMET) are associated with a high risk of metastasis and recurrence for children and young adults with papillary thyroid carcinoma. Clin Endocrinol (Oxf). 2000;53:635–644.

    Article  CAS  Google Scholar 

  29. Ferracini R, Di Renzo MF, Scotlandi K, Baldini N, Olivero M, Lollini P, Cremona O, Campanacci M, Comoglio PM. The Met/HGF receptor is over-expressed in human osteosarcomas and is activated by either a paracrine or an autocrine circuit. Oncogene. 1995;10:739–749.

    CAS  PubMed  Google Scholar 

  30. Di Renzo MF, Olivero M, Giacomini A, Porte H, Chastre E, Mirossay L, Nordlinger B, Bretti S, Bottardi S, Giordano S, et al. Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin Cancer Res. 1995; 1:147–154.

    PubMed  Google Scholar 

  31. Di Renzo MF, Olivero M, Katsaros D, Crepaldi T, Gaglia P, Zola P, Sismondi P, Comoglio PM. Overexpression of the Met/HGF receptor in ovarian cancer. Int J Cancer. 1994;58:658–662.

    PubMed  Google Scholar 

  32. Ma PC, Kijima T, Maulik G, Fox EA, Sattler M, Griffin JD, Johnson BE, Salgia R. c-MET mutaional anlysis in small cell lung cancer: Novel juxtamembrance domain mutations regulating cytoskeletal functions. Cancer Research. 2003;63:(in press).

    Google Scholar 

  33. Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, Sonoda Y, Fujimoto T, Misawa S. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911–1918.

    CAS  PubMed  Google Scholar 

  34. Yokota S, Kiyoi H, Nakao M, Iwai T, Misawa S, Okuda T, Sonoda Y, Abe T, Kahsima K, Matsuo Y, Naoe T. Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines. Leukemia. 1997;11:1605–1609.

    Article  CAS  PubMed  Google Scholar 

  35. Schmidt L, Junker K, Nakaigawa N, Kinjerski T, Weirich G, Miller M, Lubensky I, Neumann HP, Brauch H, Decker J, Vocke C, Brown JA, Jenkins R, Richard S, Bergerheim U, Gerrard B, Dean M, Linehan WM, Zbar B. Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene. 1999;18:2343–2350

    CAS  PubMed  Google Scholar 

  36. Lee JH, Han SU, Cho H, Jennings B, Gerrard B, Dean M, Schmidt L, Zbar B, Vande Woude GF. A novel germ line juxtamembrane Met mutation in human gastric cancer. Oncogene. 2000;19:4947–4953.

    CAS  PubMed  Google Scholar 

  37. Lee CC, Yamada KM. Identification of a novel type of alternative splicing of a tyrosine kinase receptor. Juxtamembrane deletion of the c-met protein kinase C serine phosphorylation regulatory site. J Biol Chem. 1994;269:19457–19461.

    CAS  PubMed  Google Scholar 

  38. Lee CC, Yamada KM. Alternatively spliced juxtamembrane domain of a tyrosine kinase receptor is a multifunctional regulatory site. Deletion alters cellular tyrosine phosphorylation pattern and facilitates binding of phosphatidylinositol-3-OH kinase to the hepatocyte growth factor receptor. J Biol Chem. 1995;270:507–510.

    CAS  PubMed  Google Scholar 

  39. effers M, Fiscella M, Webb CP, Anver M, Koochekpour S, Vande Woude GF. The mutationally activated Met receptor mediates motility and metastasis. Proc Natl Acad Sci USA. 1998;95:14417–14422.

    Google Scholar 

  40. Schmidt L, Junker K, Weirich G, Glenn G, Choyke P, Lubensky I, Zhuang Z, Jeffers M, Vande Woude G, Neumann H, Walther M, Linehan WM, Zbar B. Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res. 1998;58:1719–1722.

    CAS  PubMed  Google Scholar 

  41. Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer. SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Zbar B, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997;16:68–73.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  43. Parsons JT, Martin KH, Slack JK, Taylor JM, Weed SA. Focal adhesionkinase: a regulator of focal adhesion dynamics and cell movement. Oncogene. 2000;19:5606–5613

    Article  CAS  PubMed  Google Scholar 

  44. Muller M, Morotti A, Ponzetto C. Activation of NF-kappaB is essential for hepatocyte growth factor-mediated proliferation and tubulogenesis. Mol Cell Biol. 2002;22:1060–1072.

    Article  CAS  PubMed  Google Scholar 

  45. Bladt F, Riethmacher D, Isenmann S, Aguzzi A, Birchmeier C. Essential role for the c-met receptor in the migration of myogenic precursorcells into the limb bud. Nature. 1995;376:768–771.

    Article  CAS  PubMed  Google Scholar 

  46. Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E, Birchmeier C. Scatter factor/hepatocyte growth factor is essential for liver development. Nature. 1995;373:699–702.

    Article  CAS  PubMed  Google Scholar 

  47. Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T, Kitamura N. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature. 1995;373:702–705.

    Article  CAS  PubMed  Google Scholar 

  48. Maina F, Klein R. Hepatocyte growth factor, a versatile signal for developing neurons. Nat Neurosci. 1999;2:213–217.

    Article  CAS  PubMed  Google Scholar 

  49. Weisberg E, Sattler M, Ewaniuk DS, Salgia R. Role of focal adhesion proteins in signal transduction and oncogenesis. Crit Rev Oncog. 1997;8:343–358.

    CAS  PubMed  Google Scholar 

  50. Medico E, Gentile A, Lo Celso C, Williams TA, Gambarotta G, Trusolino L, Comoglio PM. Osteopontin is an autocrine mediator of hepatocyte growth factor-induced invasive growth. Cancer Res. 2001;61:5861–5868.

    CAS  PubMed  Google Scholar 

  51. Besser D, Bardelli A, Didichenko S, Thelen M, Comoglio PM, Ponzetto C, Nagamine Y. Regulation of the urokinase-type plasminogen activator gene by the oncogene Tpr-Met involves GRB2. Oncogene. 1997;14:705–711.

    Article  CAS  PubMed  Google Scholar 

  52. Dunsmore SE, Rubin JS, Kovacs SO, Chedid M, Parks WC, Welgus HG. Mechanisms of hepatocyte growth factor stimulation of keratinocyte metalloproteinase production. J Biol Chem. 1996;271:24576–24582.

    CAS  PubMed  Google Scholar 

  53. Wojta J, Nakamura T, Fabry A, Hufnagl P, Beckmann R, McGrath K, Binder BR. Hepatocyte growth factor stimulates expression of plasminogen activator inhibitor type 1 and tissue factor in HepG2 cells. Blood. 1994;84:151–157.

    CAS  PubMed  Google Scholar 

  54. Wang R, Ferrell LD, Faouzi S, Maher JJ, Bishop JM. Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice. J Cell Biol. 2001;153:1023–1034.

    Article  CAS  PubMed  Google Scholar 

  55. Yu Y, Merlino G. Constitutive c-Met signaling through a nonautocrine mechanism promotes metastasis in a transgenic transplantation model. Cancer Res. 2002;62:2951–2956.

    CAS  PubMed  Google Scholar 

  56. Tuck AB, Park M, Sterns EE, Boag A, Elliott BE. Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma. Am J Pathol. 1996;148:225–232

    CAS  PubMed  Google Scholar 

  57. Koochekpour S, Jeffers M, Rulong S, Taylor G, Klineberg E, Hudson EA, Resau JH, Vande Woude GF. Met and hepatocyte growth factor/scatter factor expression in human gliomas. Cancer Res. 1997;57:5391–5398.

    CAS  PubMed  Google Scholar 

  58. Li G, Schaider H, Satyamoorthy K, Hanakawa Y, Hashimoto K, Herlyn M. Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. Oncogene. 2001;20:8125–8135.

    CAS  PubMed  Google Scholar 

  59. Di Renzo MF, Olivero M, Martone T, Maffe A, Maggiora P, Stefani AD, Valente G, Giordano S, Cortesina G, Comoglio PM. Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene. 2000;19:1547–1555.

    PubMed  Google Scholar 

  60. Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis D, Tamagnone L, Comoglio PM. The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat Cell Biol. 2002;4:720–724.

    Article  CAS  PubMed  Google Scholar 

  61. Suh YA, Arnold RS, Lassegue B, Shi J, Xu X, Sorescu D, Chung AB, Griendling KK, Lambeth JD. Cell transformation by the superoxide-generating oxidase Mox1. Nature. 1999;401:79–82.

    CAS  PubMed  Google Scholar 

  62. Lander HM, Hajjar DP, Hempstead BL, Mirza UA, Chait BT, Campbell S, Quilliam LA. A molecular redox switch on p21ras. Structural basis for the interaction. J Biol Chem. 1997;272:4323–4326.

    Article  CAS  PubMed  Google Scholar 

  63. Denu JM, Tanner KG. Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen peroxide: evidence for a sulfenic acid intermediate and implications for redox regulation. Biochemistry. 1998;37:5633–5642.

    Article  CAS  PubMed  Google Scholar 

  64. Flohe L, Brigelius-Flohe R, Saliou C, Traber MG, Packer L. Redox regulation of NF-kappa B activation. Free Radic Biol Med. 1997;22:1115–1126.

    CAS  PubMed  Google Scholar 

  65. Nemoto S, Finkel T. Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science. 2002;295:2450–2452.

    Article  CAS  PubMed  Google Scholar 

  66. Dreher D, Junod AF. Role of oxygen free radicals in cancer development. Eur J Cancer. 1996;32A:30–38.

    CAS  PubMed  Google Scholar 

  67. Silvagno F, Follenzi A, Arese M, Prat M, Giraudo E, Gaudino G, Camussi G, Comoglio PM, Bussolino F. In vivo activation of met tyrosine kinase by heterodimeric hepatocyte growth factor molecule promotes angiogenesis. Arterioscler Thromb Vasc Biol. 1995;15:1857–1865.

    CAS  PubMed  Google Scholar 

  68. Cioce V, Csaky KG, Chan AM, Bottaro DP, Taylor WG, Jensen R, Aaronson SA, Rubin JS. Hepatocyte growth factor (HGF)/NK1 is a naturally occurring HGF/scatter factor variant with partial agonist/antagonist activity. J Biol Chem. 1996;271:13110–13115.

    CAS  PubMed  Google Scholar 

  69. Schwall RH, Chang LY, Godowski PJ, Kahn DW, Hillan KJ, Bauer KD, Zioncheck TF. Heparin induces dimerization and confers proliferative activity onto the hepatocyte growth factor antagonists NK1 and NK2. J Cell Biol. 1996;133:709–718.

    Article  CAS  PubMed  Google Scholar 

  70. 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. 1997;420:1–6

    Article  CAS  PubMed  Google Scholar 

  71. Otsuka T, Jakubczak J, Vieira W, Bottaro DP, Breckenridge D, Larochelle WJ, Merlino G. 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. 2000;20:2055–2065.

    Article  CAS  PubMed  Google Scholar 

  72. Parr C, Hiscox S, Nakamura T, Matsumoto K, Jiang WG. Nk4, a new HGF/SF variant, is an antagonist to the influence of HGF/SF on the motility and invasion of colon cancer cells. Int J Cancer. 2000;85:563–570.

    Article  CAS  PubMed  Google Scholar 

  73. Tomioka D, Maehara N, Kuba K, Mizumoto K, Tanaka M, Matsumoto K, Nakamura T. Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model. Cancer Res. 2001;61:7518–7524.

    CAS  PubMed  Google Scholar 

  74. Mark MR, Lokker NA, Zioncheck TF, Luis EA, Godowski PJ. Expression and characterization of hepatocyte growth factor receptor-IgG fusion proteins. Effects of mutations in the potential proteolytic cleavage site on processing and ligand binding. J Biol Chem. 1992;267:26166–26171.

    CAS  PubMed  Google Scholar 

  75. Michieli P, Basilico C, Pennacchietti S, Maffe A, Tamagnone L, Giordano S, Bardelli A, Comoglio PM. Mutant Met-mediated transformation is ligand-dependent and can be inhibited by HGF antagonists. Oncogene, 1999;18:5221–5231.

    Article  CAS  PubMed  Google Scholar 

  76. Abounader R, Lal B, Luddy C, Koe G, Davidson B, Rosen EM, Laterra J. In vivo targeting of SF/HGF and c-met expression via U1snRNA/ribozymes inhibits glioma growth and angiogenesis and promotes apoptosis. Faseb J. 2002;16:108–110.

    CAS  PubMed  Google Scholar 

  77. Jiang WG, Grimshaw D, Lane J, Martin TA, Abounader R, Laterra J, Mansel RE, Abounder R. A hammerhead ribozyme suppresses expression of hepatocyte growth factor/scatter factor receptor c-MET and reduces migration and invasiveness of breast cancer cells. Clin Cancer Res. 2001;7:2555–2562.

    CAS  PubMed  Google Scholar 

  78. Herynk MH, Stoeltzing O, Reinmuth N, Parikh NU, Abounader R, Laterra J, Radinsky R, Ellis LM, Gallick GE. Down-regulation of c-Met inhibits growth in the liver of human colorectal carcinoma cells. Cancer Res. 2003;63:2990–2996.

    CAS  PubMed  Google Scholar 

  79. Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC, Burrows FJ. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature. 2003;425:407–410.

    Article  CAS  PubMed  Google Scholar 

  80. An WG, Schulte TW, Neckers LM. The heat shock protein 90 antagonist geldanamycin alters chaperone association with p210bcr-abl and v-src proteins before their degradation by the proteasome. Cell Growth Differ. 2000;11:355–360.

    CAS  PubMed  Google Scholar 

  81. Blagosklonny MV, Toretsky J, Neckers L. Geldanamycin selectively destabilizes and conformationally alters mutated p53. Oncogene. 1995;11:933–939.

    CAS  PubMed  Google Scholar 

  82. Isaacs JS, Xu W, Neckers L. Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell. 2003;3:213–217.

    Article  CAS  PubMed  Google Scholar 

  83. Workman P. Auditing the pharmacological accounts for Hsp90 molecular chaperone inhibitors: unfolding the relationship between pharmacokinetics and pharmacodynamics. Mol Cancer Ther. 2003;2:131–138.

    CAS  PubMed  Google Scholar 

  84. Neckers L, Schulte TW, Mimnaugh E. Geldanamycin as a potential anti-cancer agent: its molecular target and biochemical activity. Invest New Drugs. 1999;17:361–373.

    Article  CAS  PubMed  Google Scholar 

  85. Webb CP, Hose CD, Koochekpour S, Jeffers M, Oskarsson M, Sausville E, Monks A, Vande Woude GF. The geldanamycins are potent inhibitors of the hepatocyte growth factor/scatter factor-met-urokinase plasminogen activator-plasmin proteolytic network. Cancer Res. 2000;60:342–349.

    CAS  PubMed  Google Scholar 

  86. Morotti A, Mila S, Accornero P, Tagliabue E, Ponzetto C. K252a inhibits the oncogenic properties of Met, the HGF receptor. Oncogene. 2002;21:4885–4893.

    Article  CAS  PubMed  Google Scholar 

  87. Sattler M, Pride YB, Ma P, Gramlich JL, Chu SC, Quinnan LA, Shirazian S, Liang C, Podar K, Christensen JG, Salgia R. A novel small molecule met inhibitor induces apoptosis in cells transformed by the oncogenic TPR-MET tyrosine kinase. Cancer Res. 2003;63:5462–5469.

    CAS  PubMed  Google Scholar 

  88. Christensen JK, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, Chen J, Wang X, Ruslim L, Blake R, Lipson KE, Ramphal J, Do S, Cui JJ, Cherrington JM, Mendel DB. A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive anti-tumor activity in vivo. Cancer Research. 2003;63:(in press)

    Google Scholar 

  89. Bardelli A, Longati P, Williams TA, Benvenuti S, Comoglio PM. A peptide representing the carboxyl-terminal tail of the met receptor inhibits kinase activity and invasive growth. J Biol Chem. 1999;274:29274–29281.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA

    Martin Sattler

  2. Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL

    Patrick C. Ma & Ravi Salgia

Authors
  1. Martin Sattler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrick C. Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ravi Salgia
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. M. D. Anderson Cancer Center, The University of Texas, Houston, TX, USA

    Rakesh Kumar Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Kluwer Academic Publishers

About this chapter

Cite this chapter

Sattler, M., Ma, P.C., Salgia, R. (2004). Therapeutic Targeting of the Receptor Tyrosine Kinase Met. In: Kumar, R. (eds) Molecular Targeting and Signal Transduction. Cancer Treatment and Research, vol 119. Springer, Boston, MA. https://doi.org/10.1007/1-4020-7847-1_7

Download citation

  • DOI: https://doi.org/10.1007/1-4020-7847-1_7

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4020-7822-4

  • Online ISBN: 978-1-4020-7847-7

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation