title: MET amplification as a potential therapeutic target in gastric cancer.
abstract: Our aim was to investigate both the prevalence of MET amplification in gastric cancer as well as the potential of this genetic alteration to serve as a therapeutic target in gastric cancer. MET amplification was assessed by initial screening with a PCR-based copy number assay followed by confirmatory FISH analysis in formalin-fixed, paraffin-embedded specimens of gastric cancer obtained at surgery. The effects of MET tyrosine kinase inhibitors (MET-TKIs) in gastric cancer cells with or without MET amplification were also examined. The median MET copy number in 266 cases of gastric cancer was 1.7, with a range of 0.41 to 21.3. We performed FISH analysis for the 15 cases with the highest MET copy numbers. MET amplification was confirmed in the four assessable cases with a MET copy number of at least 4, whereas MET amplification was not detected in those with a gene copy number of less than 4. The prevalence of MET amplification was thus 1.5% (4 out of 266 cases). Inhibition of MET by MET-TKIs resulted in the induction of apoptosis accompanied by attenuation of downstream MET signaling in gastric cancer cell lines with MET amplification but not in those without this genetic change. MET amplification identifies a small but clinically important subgroup of gastric cancer patients who are likely to respond to MET-TKIs. Furthermore, screening with a PCR-based copy number assay is an efficient way to reduce the number of patients requiring confirmation of MET amplification by FISH analysis.
authors: Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, Japan.
authors: Hisato
authors: H
authors: Kawakami
authors: Isamu
authors: I
authors: Okamoto
authors: Tokuzo
authors: T
authors: Arao
authors: Wataru
authors: W
authors: Okamoto
authors: Kazuko
authors: K
authors: Matsumoto
authors: Hirokazu
authors: H
authors: Taniguchi
authors: Kiyoko
authors: K
authors: Kuwata
authors: Haruka
authors: H
authors: Yamaguchi
authors: Kazuto
authors: K
authors: Nishio
authors: Kazuhiko
authors: K
authors: Nakagawa
authors: Yasuhide
authors: Y
authors: Yamada
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056915:DNA Copy Number Variations; D004305:Dose-Response Relationship, Drug; D005260:Female; D005784:Gene Amplification; D006801:Humans; D015151:Immunoblotting; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D016612:Paraffin Embedding; D010766:Phosphorylation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014230:Triazoles / Q000494:pharmacology
chemical_list: C547925:6-(6-(1-methyl-1H-pyrazol-4-yl)-(1,2,4)triazolo(4,3-b)pyridazin-3-ylsulfanyl)quinoline; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D014230:Triazoles; D019859:Proto-Oncogene Proteins c-met