Oncogene swap as a novel mechanism of acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor in lung cancer
Oncogene swap as a novel mechanism of acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor in lung cancer
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DOI：
10.1111/cas.12905
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发表时间：
2016-04-01
期刊：
影响因子：
5.7
通讯作者：
Mitsudomi, Tetsuya
中科院分区：
文献类型：
--
作者：
Mizuuchi, Hiroshi;Suda, Kenichi;Mitsudomi, Tetsuya
突变型选择性表皮生长因子受体酪氨酸激酶抑制剂 (EGFR-TKI)，例如罗西替尼和 AZD9291，对具有 T790M 二次突变且对第一代 EGFR-TKI 耐药的肿瘤有效。然而，考虑到癌细胞的高适应性，预计会对这些前瞻性药物产生耐药性，并且其机制在很大程度上仍不清楚。在此，通过将含有外显子 19 缺失和 T790M 的 HCC827EPR 细胞长期暴露于 CNX-2006，建立了 CNX-2006（rociletinib 的工具化合物）耐药亚系。通过对这些耐药亚克隆的分析，我们发现了两种伴随 MET 扩增的耐药机制。一种是除 T790M 之外通过 MET 扩增产生的旁路信号传导，该信号被 CNX-2006 和 MET-TKI 的组合抑制。另一个是在获得 MET 扩增时，扩增的 EGFR 突变等位基因（包括 T790M）丢失。有趣的是，单独使用 MET-TKI 就能够克服这种耐药性，这表明致癌依赖性完全从 EGFR 转移到 MET。我们建议将这种现象描述为“癌基因交换”。此外，我们分析了一名因吉非替尼获得性耐药而死亡的患者的多个病变，然后发现了一个癌基因交换的临床例子，其中EGFR突变丢失，并获得了MET基因拷贝。总之，从 EGFR 到 MET 的“癌基因交换”是 EGFR-TKI 的一种新型耐药机制。应考虑这种新机制，以避免对原始癌基因的无效抑制。
Mutant selective epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as rociletinib and AZD9291, are effective for tumors with T790M secondary mutation that become refractory to first-generation EGFR-TKI. However, acquired resistance to these prospective drugs is anticipated considering the high adaptability of cancer cells and the mechanisms remain largely obscure. Here, CNX-2006 (tool compound of rociletinib) resistant sublines were established by chronic exposure of HCC827EPR cells harboring exon 19 deletion and T790M to CNX-2006. Through the analyses of these resistant subclones, we identified two resistant mechanisms accompanied by MET amplification. One was bypass signaling by MET amplification in addition to T790M, which was inhibited by the combination of CNX-2006 and MET-TKI. Another was loss of amplified EGFR mutant allele including T790M while acquiring MET amplification. Interestingly, MET-TKI alone was able to overcome this resistance, suggesting that oncogenic dependence completely shifted from EGFR to MET. We propose describing this phenomenon as an "oncogene swap."Furthermore, we analyzed multiple lesions from a patient who died of acquired resistance to gefitinib, then found a clinical example of an oncogene swap in which the EGFR mutation was lost and a MET gene copy was gained. In conclusion, an "oncogene swap" from EGFR to MET is a novel resistant mechanism to the EGFR-TKI. This novel mechanism should be considered in order to avoid futile inhibition of the original oncogene.