Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.
Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.
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DOI：
10.1126/scitranslmed.3002003
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发表时间：
2011-03-23
影响因子：
17.1
通讯作者：
Engelman JA
中科院分区：
文献类型：
--
作者：
Sequist LV;Waltman BA;Dias-Santagata D;Digumarthy S;Turke AB;Fidias P;Bergethon K;Shaw AT;Gettinger S;Cosper AK;Akhavanfard S;Heist RS;Temel J;Christensen JG;Wain JC;Lynch TJ;Vernovsky K;Mark EJ;Lanuti M;Iafrate AJ;Mino-Kenudson M;Engelman JA
携带表皮生长因子受体（EGFR）突变的肺癌对EGFR酪氨酸激酶抑制剂有反应，但总是出现耐药性。为了阐明获得性耐药的机制，我们对37例携带EGFR突变的耐药非小细胞肺癌（NSCLC）患者的肿瘤活检进行了系统的遗传学和组织学分析。所有耐药肿瘤均保留了其原始的激活EGFR突变，并且一些获得了已知的耐药机制，包括EGFR T790M突变或MET基因扩增。一些耐药癌症显示出意想不到的遗传变化，包括EGFR扩增和PIK3CA基因突变，而其他癌症则发生了明显的上皮细胞向间充质细胞的转化。令人惊讶的是，五种耐药肿瘤（14%）从NSCLC转化为小细胞肺癌（SCLC），并且对标准SCLC治疗敏感。在三名患者中，连续活检显示，在没有EGFR抑制剂治疗的持续选择性压力的情况下，耐药的遗传机制丢失，并且这种癌症对EGFR抑制剂的第二轮治疗敏感。总的来说，这些结果加深了我们对EGFR抑制剂耐药性的理解，并强调了在整个疾病过程中反复评估癌症的重要性。
Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitors, but drug resistance invariably emerges. To elucidate mechanisms of acquired drug resistance, we performed systematic genetic and histological analyses of tumor biopsies from 37 patients with drug-resistant non–small cell lung cancers (NSCLCs) carrying EGFR mutations. All drug-resistant tumors retained their original activating EGFR mutations, and some acquired known mechanisms of resistance including the EGFR T790M mutation or MET gene amplification. Some resistant cancers showed unexpected genetic changes including EGFR amplification and mutations in the PIK3CA gene, whereas others underwent a pronounced epithelial-to-mesenchymal transition. Surprisingly, five resistant tumors (14%) transformed from NSCLC into small cell lung cancer (SCLC) and were sensitive to standard SCLC treatments. In three patients, serial biopsies revealed that genetic mechanisms of resistance were lost in the absence of the continued selective pressure of EGFR inhibitor treatment, and such cancers were sensitive to a second round of treatment with EGFR inhibitors. Collectively, these results deepen our understanding of resistance to EGFR inhibitors and underscore the importance of repeatedly assessing cancers throughout the course of the disease.
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影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
影响因子：
50.3
作者：
Carretero J;Shimamura T;Rikova K;Jackson AL;Wilkerson MD;Borgman CL;Buttarazzi MS;Sanofsky BA;McNamara KL;Brandstetter KA;Walton ZE;Gu TL;Silva JC;Crosby K;Shapiro GI;Maira SM;Ji H;Castrillon DH;Kim CF;García-Echeverría C;Bardeesy N;Sharpless NE;Hayes ND;Kim WY;Engelman JA;Wong KK
通讯作者：
Wong KK
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
51.1
作者：
Mitsudomi, Tetsuya;Morita, Satoshi;Fukuoka, Masahiro
通讯作者：
Fukuoka, Masahiro
影响因子：
158.5
作者：
Kobayashi, S;Boggon, TJ;Halmos, B
通讯作者：
Halmos, B