Department of Oncology, University of Torino, Torino, Italy.
Cancer Discov. 2013 Jun;3(6):658-73. doi: 10.1158/2159-8290.CD-12-0558. Epub 2013 Jun 2.
EGF receptor (EGFR)-targeted monoclonal antibodies are effective in a subset of metastatic colorectal cancers. Inevitably, all patients develop resistance, which occurs through emergence of KRAS mutations in approximately 50% of the cases. We show that amplification of the MET proto-oncogene is associated with acquired resistance in tumors that do not develop KRAS mutations during anti-EGFR therapy. Amplification of the MET locus was present in circulating tumor DNA before relapse was clinically evident. Functional studies show that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo. Notably, in patient-derived colorectal cancer xenografts, MET amplification correlated with resistance to EGFR blockade, which could be overcome by MET kinase inhibitors. These results highlight the role of MET in mediating primary and secondary resistance to anti-EGFR therapies in colorectal cancer and encourage the use of MET inhibitors in patients displaying resistance as a result of MET amplification.
表皮生长因子受体 (EGFR)-靶向单克隆抗体在一部分转移性结直肠癌中有效。不可避免的是，所有患者都会产生耐药性，大约 50%的病例会出现 KRAS 突变。我们表明，在接受抗 EGFR 治疗期间未发生 KRAS 突变的肿瘤中，MET 原癌基因的扩增与获得性耐药有关。在临床上明显复发之前，循环肿瘤 DNA 中就存在 MET 基因扩增。功能研究表明，MET 激活导致体外和体内抗 EGFR 治疗耐药。值得注意的是，在患者来源的结直肠癌细胞异种移植模型中，MET 扩增与 EGFR 阻断耐药相关，MET 激酶抑制剂可克服这种耐药性。这些结果强调了 MET 在介导结直肠癌对抗 EGFR 治疗的原发性和继发性耐药中的作用，并鼓励在因 MET 扩增而出现耐药的患者中使用 MET 抑制剂。
