Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR-Mutant Lung Cancer.
Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR-Mutant Lung Cancer.
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DOI：
10.1158/2159-8290.cd-15-0063
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发表时间：
2015-09
期刊：
影响因子：
28.2
通讯作者：
Jänne PA
中科院分区：
文献类型：
--
作者：
Tricker EM;Xu C;Uddin S;Capelletti M;Ercan D;Ogino A;Pratilas CA;Rosen N;Gray NS;Wong KK;Jänne PA
不可逆的基于嘧啶的EGFR抑制剂，包括WZ 4002，选择性抑制EGFR活化和EGFR抑制剂抗性T790 M突变，比野生型EGFR更有效。虽然这类突变选择性EGFR抑制剂在携带EGFR T790 M的肺癌患者中临床有效，但先前的临床前研究表明，通过激活ERK 1/2信号的基因组改变可发生获得性耐药。我们发现WZ 4002处理后ERK 1/2的再激活迅速发生。MEK抑制剂曲美替尼对ERK 1/2的伴随抑制可防止ERK 1/2再活化，增强WZ 4002诱导的细胞凋亡，并抑制已知通过T790 M依赖性和非依赖性机制获得耐药性的WZ 4002敏感模型中耐药性的出现。对WZ 4002与曲美替尼组合的耐药性最终由于AKT/mTOR再活化而出现。这些数据表明，EGFR和MEK的初始共靶向可以显著阻止突变EGFR肺癌中获得性耐药的发展。
Irreversible pyrimidine based EGFR inhibitors, including WZ4002, selectively inhibit both EGFR activating and EGFR inhibitor resistant T790M mutations more potently than wild type EGFR. While this class of mutant selective EGFR inhibitors is effective clinically in lung cancer patients harboring EGFR T790M, prior preclinical studies demonstrate that acquired resistance can occur through genomic alterations that activate ERK1/2 signaling. Here we find that ERK1/2 reactivation occurs rapidly following WZ4002 treatment. Concomitant inhibition of ERK1/2 by the MEK inhibitor trametinib prevents ERK1/2 reactivation, enhances WZ4002 induced apoptosis and inhibits the emergence of resistance in WZ4002 sensitive models known to acquire resistance via both T790M dependent and independent mechanisms. Resistance to WZ4002 in combination with trametinib eventually emerges due to AKT/mTOR reactivation. These data suggest that initial co-targeting of EGFR and MEK could significantly impede the development of acquired resistance in mutant EGFR lung cancer.