PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR.
PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR.
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DOI：
10.1158/0008-5472.can-08-4055
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发表时间：
2009-04-15
期刊：
影响因子：
11.2
通讯作者：
Thomas RK
中科院分区：
文献类型：
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作者：
Sos ML;Koker M;Weir BA;Heynck S;Rabinovsky R;Zander T;Seeger JM;Weiss J;Fischer F;Frommolt P;Michel K;Peifer M;Mermel C;Girard L;Peyton M;Gazdar AF;Minna JD;Garraway LA;Kashkar H;Pao W;Meyerson M;Thomas RK
肺癌对表皮生长因子受体(EGFR)抑制的临床耐药与EGFR T790M耐药突变或MET扩增有关。导致EGFR抑制剂耐药性的其他机制仍然难以捉摸。通过联合应用基因表达、拷贝数和EGFR抑制反应性的生化分析，我们鉴定了PTEN的纯合缺失，以分离EGFR依赖和EGFR非依赖的细胞。我们发现，在EGFR依赖的细胞中，PTEN的丢失部分地将突变的EGFR从下游信号中分离出来，并激活了EGFR，从而促进了对厄洛替尼的耐药性。在24例原发EGFR突变的非小细胞肺癌(NSCLC)肿瘤中观察到1例PTEN缺失，支持了我们的研究结果的临床相关性。这些结果表明，在EGFR突变的NSCLC中存在一种新的耐药机制，涉及PTEN缺失。
Clinical resistance to epidermal growth factor receptor (EGFR) inhibition in lung cancer has been linked to the emergence of the EGFR T790M resistance mutation or amplification of MET. Additional mechanisms contributing to EGFR inhibitor resistance remain elusive. By applying combined analyses of gene expression, copy number, and biochemical analyses of EGFR inhibitor responsiveness, we identified homozygous loss of PTEN to segregate EGFR-dependent and EGFR-independent cells. We show that in EGFR-dependent cells, PTEN loss partially uncouples mutant EGFR from downstream signaling and activates EGFR, thereby contributing to erlotinib resistance. The clinical relevance of our findings is supported by the observation of PTEN loss in 1 out of 24 primary EGFR-mutant non–small cell lung cancer (NSCLC) tumors. These results suggest a novel resistance mechanism in EGFR-mutant NSCLC involving PTEN loss.