Faber Anthony C, Li Danan, Song Youngchul, Liang Mei-Chih, Yeap Beow Y, Bronson Roderick T, Lifshits Eugene, Chen Zhao, Maira Sauveur-Michel, García-Echeverría Carlos, Wong Kwok-Kin, Engelman Jeffrey A
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19503-8. doi: 10.1073/pnas.0905056106. Epub 2009 Oct 22.
Non-small cell lung cancers with activating mutations in the epidermal growth factor receptor (EGFR) are highly responsive to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Such cancers are "addicted" to EGFR, and treatment with a TKI invariably leads to down-regulation of the PI3K-AKT-mTOR and MEK-ERK signaling pathways, resulting in apoptosis. Using a dual PI3K-mTOR inhibitor, NVP-BEZ235, we evaluated whether PI3K-mTOR inhibition alone induced apoptosis in these cancers. In contrast to HER2-amplified breast cancers, we found that PI3K-mTOR inhibition did not promote substantial apoptosis in the EGFR mutant lung cancers. However, blocking both PI3K-mTOR and MEK simultaneously led to apoptosis to similar levels as the EGFR TKIs, suggesting that down-regulation of these pathways may account for much of the apoptosis promoted by EGFR inhibition. In EGFR mutant lung cancers, down-regulation of both intracellular pathways converged on the BH3 family of proteins regulating apoptosis. PI3K inhibition led to down-regulation of Mcl-1, and MEK inhibition led to up-regulation of BIM. In fact, down-regulation of Mcl-1 by siRNA was sufficient to sensitize these cancers to single-agent MEK inhibitors. Surprisingly, an AKT inhibitor did not decrease Mcl-1 levels, and when combined with MEK inhibitors, failed to induce apoptosis. Importantly, we observed that the combination of PI3K-mTOR and MEK inhibitors effectively shrunk tumors in a transgenic and xenograft model of EGFR T790M-L858R cancers. These data indicate simultaneous inhibition of PI3K-mTOR and MEK signaling is an effective strategy for treating EGFR mutant lung cancers, including those with acquired resistance to EGFR TKIs.
具有表皮生长因子受体（EGFR）激活突变的非小细胞肺癌对EGFR酪氨酸激酶抑制剂（TKIs），如吉非替尼和厄洛替尼，高度敏感。这类癌症对EGFR“成瘾”，用TKI治疗总是会导致PI3K-AKT-mTOR和MEK-ERK信号通路下调，从而引发细胞凋亡。我们使用双重PI3K-mTOR抑制剂NVP-BEZ235，评估单独抑制PI3K-mTOR是否能在这些癌症中诱导细胞凋亡。与HER2扩增的乳腺癌不同，我们发现抑制PI3K-mTOR在EGFR突变的肺癌中不会促进大量细胞凋亡。然而，同时阻断PI3K-mTOR和MEK会导致与EGFR TKIs相似水平的细胞凋亡，这表明这些信号通路的下调可能是EGFR抑制所促进的大部分细胞凋亡的原因。在EGFR突变的肺癌中，两条细胞内信号通路的下调都集中在调节细胞凋亡的BH3蛋白家族上。抑制PI3K会导致Mcl-1下调，抑制MEK会导致BIM上调。事实上，通过小干扰RNA（siRNA）下调Mcl-1足以使这些癌症对单药MEK抑制剂敏感。令人惊讶的是，一种AKT抑制剂并没有降低Mcl-1水平，并且与MEK抑制剂联合使用时未能诱导细胞凋亡。重要的是，我们观察到PI3K-mTOR和MEK抑制剂的联合用药在EGFR T790M-L858R癌症的转基因和异种移植模型中有效地使肿瘤缩小。这些数据表明，同时抑制PI3K-mTOR和MEK信号是治疗EGFR突变肺癌的有效策略，包括那些对EGFR TKIs获得性耐药的肺癌。
