Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition
Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition
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DOI：
10.1073/pnas.0905056106
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发表时间：
2009-11-17
影响因子：
11.1
通讯作者：
Engelman, Jeffrey A.
中科院分区：
文献类型：
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作者：
Faber, Anthony C.;Li, Danan;Engelman, Jeffrey A.
在表皮生长因子受体（EGFR）中具有激活突变的非小细胞肺癌对EGFR酪氨酸激酶抑制剂（TKI）（如吉非替尼和厄洛替尼）高度敏感。此类癌症对EGFR“成瘾”，并且用TKI治疗总是导致PI 3 K-AKT-mTOR和MEK-ERK信号传导途径的下调，从而导致细胞凋亡。使用双重PI 3 K-mTOR抑制剂NVP-BEZ 235，我们评估了单独的PI 3 K-mTOR抑制是否在这些癌症中诱导细胞凋亡。与HER 2扩增的乳腺癌相反，我们发现PI 3 K-mTOR抑制并不促进EGFR突变型肺癌的实质性细胞凋亡。然而，阻断PI 3 K-mTOR和MEK同时导致细胞凋亡达到与EGFR TKI相似的水平，表明这些途径的下调可能是EGFR抑制促进的细胞凋亡的主要原因。在EGFR突变型肺癌中，两种细胞内途径的下调集中在调节细胞凋亡的蛋白质BH 3家族上。PI 3 K抑制导致Mcl-1下调，MEK抑制导致BIM上调。事实上，通过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，AKT抑制剂不降低Mcl-1水平，并且当与MEK抑制剂组合时，不能诱导细胞凋亡。重要的是，我们观察到PI 3 K-mTOR和MEK抑制剂的组合在EGFR T790 M-L 858 R癌症的转基因和异种移植模型中有效地缩小了肿瘤。这些数据表明同时抑制PI 3 K-mTOR和MEK信号传导是治疗EGFR突变型肺癌的有效策略，包括对EGFR TKI具有获得性耐药性的那些。
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.