EGFR TKI耐药的新机制-致癌基因换位

http://www.ncbi.nlm.nih.gov/pubmed/26845230
Cancer Sci. 2016 Feb 4. doi: 10.1111/cas.12905.
Oncogene swap as a novel mechanism of acquired resistance to EGFR-tyrosine kinase inhibitor in lung cancer
Abstract
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-TKIs. 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 to describe this phenomenon as "oncogene swap". Furthermore, we analyzed multiple lesions from a patient who died of acquired resistance to gefitinib, then found a clinical example of oncogene swap in which the EGFR mutation was lost and a MET gene copy was gained. In conclusion, "oncogene swap" from EGFR to MET is a novel resistant mechanism to the EGFR-TKIs. This possibility should be considered in order to avoid futile inhibition of the original oncogene.
文中指出第三代EGFR TKI的耐药机制还很不明确。 本文使用HCC827 EPR 外显子19突变和T790M肿瘤细胞缓慢暴露于CNX-2006 (rociletinib-1686非正版)而建立耐药的细胞亚组。通过对这些亚组的分析，我们发现由MET的2种耐药机制。一是除T790M外由MET扩增导致的信号旁通，被CNX-2006和MET-TKI 联合抑制。另一是扩增的EGFR突变等位基因包括获得MET扩增的T790M的丢失，有趣的是MET-TKI单药就能够克服耐药，提示致癌基因对EGFR的依赖完全转移到MET.我们描述这种现象为-致癌基因转换。而且，我们分析取自于一个死于吉非替尼耐药的患者的多个组织，也发现这种现象EGFR突变丢失而MET获得。 总之，致癌基因转换-从EGFR 到 MET是个新的EGFR-TKIs耐药机制。

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