Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.
Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.
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DOI：
10.1158/2159-8290.cd-12-0558
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发表时间：
2013-06
期刊：
影响因子：
28.2
通讯作者：
Siena S
中科院分区：
文献类型：
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作者：
Bardelli A;Corso S;Bertotti A;Hobor S;Valtorta E;Siravegna G;Sartore-Bianchi A;Scala E;Cassingena A;Zecchin D;Apicella M;Migliardi G;Galimi F;Lauricella C;Zanon C;Perera T;Veronese S;Corti G;Amatu A;Gambacorta M;Diaz LA Jr;Sausen M;Velculescu VE;Comoglio P;Trusolino L;Di Nicolantonio F;Giordano S;Siena S
EGFR靶向单克隆抗体在转移性结直肠肿瘤（mCRC）的子集中有效。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。我们发现MET原癌基因的扩增与抗EGFR治疗期间未发生KRAS突变的患者的获得性耐药相关。MET基因座的扩增存在于复发前的循环肿瘤DNA中，临床上是明显的。功能性研究表明，MET活化在体外和体内均赋予对抗EGFR治疗的抗性。值得注意的是，在患者来源的CRC异种移植物中，MET扩增与对EGFR阻断的耐药性相关，这可以通过MET激酶抑制剂克服。这些结果突出了MET在介导CRC中抗EGFR治疗的原发性和继发性耐药中的作用，并鼓励在因MET扩增而显示耐药的患者中使用MET抑制剂。
EGFR targeted monoclonal antibodies are effective in a subset of metastatic colorectal tumors (mCRC). 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 patients who 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 demonstrate that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo. Notably, in patient-derived CRC 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 CRC and encourage the use of MET inhibitors in patients displaying resistance as a result of MET amplification.