MET amplification as a potential therapeutic target in gastric cancer

// Hisato Kawakami 1 , Isamu Okamoto 1 , Tokuzo Arao 2 , Wataru Okamoto 1 , Kazuko Matsumoto 2 , Hirokazu Taniguchi 4 , Kiyoko Kuwata 1 , Haruka Yamaguchi 1 , Kazuto Nishio 2 , Kazuhiko Nakagawa 1 , and Yasuhide Yamada 3 1 Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, Japan; 2 Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, Japan; 3 Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan 4 Department of Pathology, National Cancer Center Hospital, Tokyo, Japan Correspondence: Isamu Okamoto, email: // Keywords : MET, gastric cancer, gene amplification, FISH, PCR Received : October 24, 2012, Accepted : November 15, 2012, Published : November 17, 2012 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 <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.