title: MET-targeted therapy for gastric cancer: the importance of a biomarker-based strategy.
abstract: The MET protooncogene encodes the receptor tyrosine kinase c-MET (MET). Aberrant activation of MET signaling occurs in a subset of advanced malignancies, including gastric cancer, and promotes tumor cell growth, survival, migration, and invasion as well as tumor angiogenesis, suggesting its potential importance as a therapeutic target. MET can be activated by two distinct pathways that are dependent on or independent of its ligand, hepatocyte growth factor (HGF), with the latter pathway having been attributed mostly to MET amplification in gastric cancer. Preclinical evidence has suggested that interruption of the HGF-MET axis either with antibodies to HGF or with MET tyrosine kinase inhibitors (TKIs) has antitumor effects in gastric cancer cells. Overexpression of MET occurs frequently in gastric cancer and has been proposed as a potential predictive biomarker for anti-MET therapy. However, several factors can trigger such MET upregulation in a manner independent of HGF, suggesting that gastric tumors with MET overexpression are not necessarily MET driven. On the other hand, gastric cancer cells with MET amplification are dependent on MET signaling for their survival and are thus vulnerable to MET TKI treatment. Given the low prevalence of MET amplification in gastric cancer (approximately 8 %), testing for this genetic change would substantially narrow the target population but it might constitute a better biomarker than MET overexpression for MET TKI therapy. We compare aberrant MET signaling dependent on the HGF-MET axis or on MET amplification as well as address clinical issues and challenges associated with the identification of appropriate biomarkers for MET-driven tumors.
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
authors.forename: Hisato
authors.initials: H
authors.lastname: Kawakami
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, 812-8582, Japan. okamotoi@kokyu.med.kyushu-u.ac.jp.
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: Amplification; Gastric cancer; Hepatocyte growth factor; MET