- Letter to the Editor
- Open Access
Infectious Agents and Cancer volume 8, Article number: 13 (2013)
c-Met is a receptor tyrosine kinase that encodes protein such as hepatocyte growth factor receptor (HGFR). Inappropriate activity of c-Met can cause wide variety of carcinomas. c-Met inhibitor are relatively new class of small molecules that inhibit the enzymatic activity of c-Met tyrosine kinase. Met inhibitors divided into two main classes: class I (SU-11274-like) and class II (AM7-like). The use of c-Met inhibitors with other therapeutic agents could be crucial for overcoming potential resistance as well as for improving overall clinical benefit. Met pathway inhibitors might be used in combination with other treatments, including chemo-, radio- or immunotherapy
Letter to editor
c-Met is a proto-oncogene that encode a protien known as hepatocyte growth factor receptor (HGFR) [1–3]. It is essential for embryonic development, wound healing and organ morphogenesis [4, 5]. MET is a membrane receptor. It stimulates cell scattering, invasion, protection from apoptosis and angiogenesis . MET is normally expressed by cells of epithelial origin . Deregulated activity of c-Met can cause a wide variety of different cancers, such as colorectal, thyroid, renal cell, ovary, breast, pancreas, prostate, liver, and melanoma and in gastric carcinoma [7–11].
Hepatocyte growth factor (HGF) is the only known ligand of the MET receptor [4, 5, 12]. Upon HGF stimulation, MET induces MET kinase catalytic activity which triggers transphosphorylation of the tyrosine Tyr 1234 and Tyr 1235. These two tyrosines engage various signal transducers, thus initiating a whole spectrum of biological activities driven by MET, collectively known as the invasive growth program. Over expression, gene amplification, mutation, a ligand-dependent auto- or paracrine loop or an untimely activation of RTK leads to c-Met dysregulation [4, 13]. Cancer development is closely associated with different oncogenic pathways. RAS pathway mediates scattering and proliferation signals which lead to branch morphogenesis . PICK3 pathways activates either directly or through down stream of RAS pathway . Beta catenin pathway participates in transcriptional regulation of numerous genes while NOTCH pathway activates through Delta ligand [16, 17]. Activation of these oncogenic pathways (RAS, PI3K, STAT3, beta-catenin), angiogenesis and cells dissociation due to metalloprotease production, which often leads to metastasis, are involved in the development of cancer .
c-Met inhibitors are relatively new class of small molecules that inhibit the enzymatic activity of the c-Met tyrosine kinase. Pyrrole-indolinone (PHA-665752) is a prototype selective class of inhibitors that inhibits HGF/SF-induced receptor phosphorylation [4, 5, 19]. There are basically two classes of c-Met inhibitors, ATP competitive and ATP non-competitive inhibitor. ATP competitive inhibitors are further divided into two classes; class I (SU-11274-like) and class II (AM7-like) on the basis of different types of binding and a third group of non-competitive ATP inhibitor that binds in a different way to the other two [20, 21]. Class I inhibitors are selective, U-shaped and attached to the activation loop of c-Met. JNJ-38877605 ( for advanced and refractory solid tumors) and PF-04217903 are class I met inhibitors that underwent phase I clinical trials in 2010 . Class II inhibitors have urea group in either cyclic or acyclic form. Foretinib XL880 is a class II met inhibitor that targets multiple tyrosine kinases, primary targets are MET, VEGFR2 and KDR. It has completed phase-2 clinical trial with indications for head and neck, gastric and renal cell carcinoma [22, 23]. Other candidates undergoing trials include Merck’ MK-2461, Bristol Meyers Squib’ BMS-777607, GSK/Exelixis’ GSK/1363089/XL 880 and BMS/Exelixis’ XL-184 [12, 22].
The Met pathway is one of the most frequently dysregulated pathways in human cancer . c-Met inhibitors that are currently in clinical trials include cabozantinib and foretinib. Cabozantinib (XL184) was approved by the U.S. FDA in November 2012 for the treatment of medullary thyroid cancer . Patients taking this medication should not ingest grapefruit or grapefruit juice as it may increase the concentration of the drug in the patient's blood . Foretinib is yet an experimental drug candidate for the treatment of cancer .
The use of c-Met inhibitors with other therapeutic agents could be crucial for overcoming potential resistance as well as for improving overall clinical benefit. As a key element in the development of any targeted therapy, the biochemical and molecular determination of the precise functions of the Met pathway in the context of other relevant pro-cancer pathways will undoubtedly play a significant role in this effort . More implications are likely to be discovered as new horizons in cancer therapeutics are unveiled .
Maulik G, Shrikhande A, Kijima T, Ma PC, Morrison PT, Salgia R: Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition. Cytokine Growth Factor Rev. 2002, 13 (1): 41-10.1016/S1359-6101(01)00029-6.
Galland F, Stefanova M, Lafage M, Birnbaum D: Localization of the 5’end of the MCF2 oncogene to human chromosome 15q15→ q23. Cytogenet Genome Res. 1992, 60 (2): 114-116. 10.1159/000133316.
Bottaro DP, Rubin JS, Faletto DL, Chan A, Kmiecik TE, Vande WG, Aaronson SA: Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991, 251 (4995): 802-10.1126/science.1846706. New York, NY
Porter J: Small molecule c-Met kinase inhibitors: a review of recent patents. Expert Opin Ther Pat. 2010, 20 (2): 159-177. 10.1517/13543770903514137.
Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, Chen J, Wang X, Ruslim L, Blake R: A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res. 2003, 63 (21): 7345-7355.
Comoglio PM, Giordano S, Trusolino L: Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov. 2008, 7 (6): 504-516. 10.1038/nrd2530.
Davis IJ, McFadden AW, Zhang Y, Coxon A, Burgess TL, Wagner AJ, Fisher DE: Identification of the receptor tyrosine kinase c-Met and its ligand, hepatocyte growth factor, as therapeutic targets in clear cell sarcoma. Cancer Res. 2010, 70 (2): 639-645. 10.1158/0008-5472.CAN-09-1121.
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 (12): 1547-1555. 10.1038/sj.onc.1203455.
Park WS, Dong SM, Kim SY, Na EY, Shin MS, Pi JH, Kim BJ, Bae JH, Hong YK, Lee KS: Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res. 1999, 59 (2): 307-310.
Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997, 16 (1): 68-73. 10.1038/ng0597-68.
Christensen JG, Burrows J, Salgia R: c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005, 225 (1): 1-26. 10.1016/j.canlet.2004.09.044.
Liu X, Newton RC, Scherle PA: Developing c-MET pathway inhibitors for cancer therapy: progress and challenges. Trends Mol Med. 2010, 16 (1): 37-45. 10.1016/j.molmed.2009.11.005.
Sattler M, Salgia R: The MET axis as a therapeutic target. Update Cancer Ther. 2009, 3 (3): 109-118. 10.1016/j.uct.2009.01.001.
O'Brien LE, Tang K, Kats ES, Schutz-Geschwender A, Lipschutz JH, Mostov KE: ERK and MMPs sequentially regulate distinct stages of epithelial tubule development. Dev Cell. 2004, 7 (1): 21-32. 10.1016/j.devcel.2004.06.001.
Graziani A, Gramaglia D, Cantley L, Comoglio P: The tyrosine-phosphorylated hepatocyte growth factor/scatter factor receptor associates with phosphatidylinositol 3-kinase. J Biol Chem. 1991, 266 (33): 22087-22090.
Monga SP, Mars WM, Pediaditakis P, Bell A, Mule K, Bowen WC, Wang X, Zarnegar R, Michalopoulos GK: Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes. Cancer Res. 2002, 62 (7): 2064-2071.
Abounader R, Reznik T, Colantuoni C, Martinez-Murillo F, Rosen EM, Laterra J: Regulation of c-Met-dependent gene expression by PTEN. Oncogene. 2004, 23 (57): 9173-9182.
HGF/c-Met and cancer.http://www.healthvalue.net/c-metandcancer.html,
Wang X, Le P, Liang C, Chan J, Kiewlich D, Miller T, Harris D, Sun L, Rice A, Vasile S: Potent and selective inhibitors of the Met [hepatocyte growth factor/scatter factor (HGF/SF) receptor] tyrosine kinase block HGF/SF-induced tumor cell growth and invasion. Mol Cancer Ther. 2003, 2 (11): 1085-1092.
Dussault I, Bellon SF: From concept to reality: the long road to c-Met and RON receptor tyrosine kinase inhibitors for the treatment of cancer. Anti-Cancer Agents Med Chem. 2009, 9 (2): 221-229. 10.2174/187152009787313792.
Eathiraj S, Palma R, Volckova E, Hirschi M, France DS, Ashwell MA, Chan TC: 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. 2011, 286 (23): 20666-20676. 10.1074/jbc.M110.213801.
Underiner TL, Herbertz T, Miknyoczki SJ: Discovery of small molecule c-Met inhibitors: evolution and profiles of clinical candidates. Anti-Cancer Agents Med Chem. 2010, 10 (1): 7-10.2174/1871520611009010007.
Choueiri TK, Vaishampayan U, Rosenberg JE, Logan TF, Harzstark AL, Bukowski RM: Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol. 2013, 31 (2): 181-6. 10.1200/JCO.2012.43.3383.
FDA approves Cometriq to treat rare type of thyroid cancer.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm330143.htm,
Cometriq prescribing information.http://www.exelixis.com/sites/default/files/pdf/COMETRIQ%20Prescribing%20Information.pdf,
Huang P: FORETINIB. Drugs Future. 2011, 35 (11): 893-901.
Anwer SMS, Ansari MH: Clouds with silver lining: defining conditions that serve as blessings in disguise. El Mednifico J. 2012, 1 (1): 19-
We sincerely acknowledge Hafsa Dawood for her contribution.
Authors declare they have no competing interest.
AM and HMA did manuscript drafting and AS, AMHK and SS did critical review. All have given final approval of the version to be published.