Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors.
Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors.
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DOI：
10.1158/2159-8290.cd-11-0284
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发表时间：
2012-05
期刊：
影响因子：
28.2
通讯作者：
Mellinghoff IK
中科院分区：
文献类型：
--
作者：
Vivanco I;Robins HI;Rohle D;Campos C;Grommes C;Nghiemphu PL;Kubek S;Oldrini B;Chheda MG;Yannuzzi N;Tao H;Zhu S;Iwanami A;Kuga D;Dang J;Pedraza A;Brennan CW;Heguy A;Liau LM;Lieberman F;Yung WK;Gilbert MR;Reardon DA;Drappatz J;Wen PY;Lamborn KR;Chang SM;Prados MD;Fine HA;Horvath S;Wu N;Lassman AB;DeAngelis LM;Yong WH;Kuhn JG;Mischel PS;Mehta MP;Cloughesy TF;Mellinghoff IK
胶质母细胞瘤（GBM）中表皮生长因子受体（EGFR）的激活通过细胞外（EC）结构域的突变或缺失发生。与EGFR激酶结构域（KD）突变的肺癌不同，GBM对EGFR抑制剂厄洛替尼的反应较差。使用RNAi，我们发现携带EGFR EC突变的GBM细胞显示EGFR成瘾。与在肺癌中发现的KD突变体相反，胶质瘤特异性EGFR EC突变体被靶向活性激酶构象的EGFR抑制剂（例如，厄洛替尼）。另一方面，与无活性EGFR构象结合的抑制剂有效地抑制EGFR EC突变体并诱导EGFR突变体GBM细胞中的细胞死亡。我们的研究结果为GBM中的单激酶成瘾提供了第一个证据，并表明第一代EGFR抑制剂在GBM与肺癌中令人失望的临床活性可能归因于这两种癌症类型中突变EGFR的不同构象要求。
Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain (KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). Inhibitors which bind to the inactive EGFR conformation, on the other hand, potently inhibit EGFR EC mutants and induce cell death in EGFR mutant GBM cells. Our results provide first evidence for single kinase addiction in GBM, and suggest that the disappointing clinical activity of first-generation EGFR inhibitors in GBM versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these two cancer types.