MET overexpression and amplification define a distinct molecular subgroup for targeted therapies in gastric cancer

• Published in: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 2016-07, Vol.19 (3), p.778-788
• Main Authors: Yang, Yang, Wu, Nandie, Shen, Jie, Teixido, Cristina, Sun, Xia, Lin, Zihan, Qian, Xiaoping, Zou, Zhengyun, Guan, Wenxian, Yu, Lixia, Rosell, Rafael, Liu, Baorui, Wei, Jia
• Format: Article
• Language: English
• Subjects: Abdominal Surgery; Adult; Aged; Aged, 80 and over; Animals; Apoptosis; Biomarkers, Tumor - metabolism; Blotting, Western; Cancer Research; Cell Proliferation; Drug Resistance, Neoplasm - genetics; Female; Fluorescent Antibody Technique; Follow-Up Studies; Gastric cancer; Gastroenterology; Humans; Immunoenzyme Techniques; In Situ Hybridization, Fluorescence; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplasm Grading; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Staging; Oncology; Original Article; Prognosis; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-met - metabolism; Pyrazoles - therapeutic use; Pyridines - therapeutic use; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Surgical Oncology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1436-3291; 1436-3305
• DOI: 10.1007/s10120-015-0545-5

Background Currently, only trastuzumab, ramucirumab, and apatinib effectively treat gastric cancer. Thus, additional novel targets are required for this disease. Methods We investigated the immunohistochemical and fluorescence in situ hybridization expression of MET, ROS1, and ALK in four gastric cell lines and a cohort of 98 gastric cancer patients. Crizotinib response was studied in vitro and in vivo. Results Crizotinib potently inhibited in vitro cell growth in only one cell line, which also showed MET amplification. A positive correlation between crizotinib sensitivity and MET overexpression was observed ( P  = 0.045) in the histoculture drug response assay. Meanwhile, patient-derived tumor xenograft mouse models transplanted with tissues with higher MET protein expression displayed a highly selective sensitivity to crizotinib. In the 98 patients, MET overexpression was found in 42 (42.9 %) and MET was amplified in 4 (4.1 %). ROS1 and ALK overexpression were found in 25 (25.5 %) and 0 patients, respectively. However, none of the patients screened harbored ALK or ROS1 rearrangements. No significant association was found between overall survival and MET or ROS1 status. We also observed a stage IV gastric cancer patient with MET amplification who experienced tumor shrinkage and clinical benefit after 3 weeks of crizotinib as fourth-line treatment. Conclusions Crizotinib may induce clinically relevant anticancer effects in MET-overexpressed or MET-amplified gastric cancer patients.