MET overexpression and amplification define a distinct molecular subgroup for targeted therapies in gastric cancer
MET overexpression and amplification define a distinct molecular subgroup for targeted therapies in gastric cancer
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MET 过表达和扩增定义了胃癌靶向治疗的独特分子亚组。
DOI：
10.1007/s10120-015-0545-5
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发表时间：
2016-07
期刊：
影响因子：
7.4
通讯作者：
Wei Jia
中科院分区：
文献类型：
--
作者：
Yang Yang;Wu N;ie;Shen Jie;Teixido Cristina;Sun Xia;Lin Zihan;Qian Xiaoping;Zou Zhengyun;Guan Wenxian;Yu Lixia;Rosell Rafael;Liu Baorui;Wei Jia
背景目前，只有曲妥珠单抗、雷莫芦单抗和阿帕替尼能有效治疗胃癌。因此，需要额外的新的目标，这种diseases.MethodsWe的免疫组化和荧光原位杂交表达MET，ROS 1，和ALK在四个胃细胞系和一个队列的98例胃癌患者。克唑替尼反应进行了研究，在体外和vivo.ResultsCrizotinib有效地抑制在体外细胞生长，只有一个细胞系，这也表明MET扩增。在组织培养药物反应试验中观察到克唑替尼敏感性与MET过表达之间呈正相关（P= 0.045）。同时，移植了MET蛋白表达较高的组织的患者源性肿瘤异种移植小鼠模型显示出对克唑替尼的高度选择性敏感性。在98例患者中，42例（42.9%）MET过表达，4例（4.1%）MET扩增。ROS1和ALK分别在25例（25.5%）和0例患者中发现过表达。然而，筛选的患者均未发生ALK或ROS 1重排。总生存率与MET或ROS 1状态之间无显著相关性。我们还观察到一个IV期胃癌患者MET扩增谁经历了3周的crizotinib作为第四线treatment.ConclusionsCrizotinib的肿瘤缩小和临床效益可能会引起临床相关的抗癌作用MET过表达或MET扩增的胃癌患者。
BackgroundCurrently, only trastuzumab, ramucirumab, and apatinib effectively treat gastric cancer. Thus, additional novel targets are required for this disease.MethodsWe 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.ResultsCrizotinib 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.ConclusionsCrizotinib may induce clinically relevant anticancer effects in MET-overexpressed or MET-amplified gastric cancer patients.
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