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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition
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Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition

机译：PI3K抑制后对HER2和EGFR上瘾的癌症细胞的差异诱导凋亡

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摘要

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 PBK-mTOR inhibition alone induced apoptosis in these cancers. In contrast to HER2-ampli-fied breast cancers, we found that PI3K-mTOR inhibition did not promote substantial apoptosis in the EGFR mutant lung cancers. However, blocking both PBK-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.
机译：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吉非替尼和厄洛替尼等EGFR酪氨酸激酶抑制剂（TKI）高度敏感。此类癌症“归因于” EGFR，而用TKI治疗总是导致PI3K-AKT-mTOR和MEK-ERK信号通路下调，从而导致细胞凋亡。我们使用双重PI3K-mTOR抑制剂NVP-BEZ235，评估了PBK-mTOR抑制是否单独诱导了这些癌症中的细胞凋亡。与HER2扩增的乳腺癌相比，我们发现PI3K-mTOR抑制不会促进EGFR突变型肺癌中的实质性细胞凋亡。然而，同时阻断PBK-mTOR和MEK会导致凋亡达到与EGFR TKI相似的水平，这表明这些途径的下调可能解释了EGFR抑制促进的许多凋亡。在EGFR突变型肺癌中，两种细胞内途径的下调都集中在调节细胞凋亡的BH3蛋白家族上。 PI3K抑制导致Mcl-1的下调，MEK抑制导致BIM的上调。实际上，siRNA对Mcl-1的下调足以使这些癌症对单药MEK抑制剂敏感。令人惊讶地，AKT抑制剂没有降低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PI3K-mTOR和MEK抑制剂的组合在EGFR T790M-L858R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PI3K-mTOR和MEK信号传导是治疗EGFR突变型肺癌（包括对EGFR TKI具有获得性耐药的肺癌）的有效策略。

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  • 作者

    Anthony C. Faber; Danan Li; YoungChul Song; Mei-Chih Liang; Beow Y. Yeap; Roderick T. Bronson; Eugene Lifshits; Zhao Chen; Sauveur-Michel Maira; Carlos Garcia-Echeverria; Kwok-Kin Wong; Jeffrey A. Engelman;

  • 作者单位

    Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129;

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115 Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, MA 02115;

    Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129;

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115 Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, MA 02115;

    Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129 Departments of Medicine, Harvard Medical School, Boston, MA 02115;

    Departments of Pathology, Harvard Medical School, Boston, MA 02115;

    Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129;

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115 Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, MA 02115;

    Departments of Novartis Institutes for BioMedical Research, Novartis Oncology, CH-4002 Basel, Switzerland;

    Departments of Novartis Institutes for BioMedical Research, Novartis Oncology, CH-4002 Basel, Switzerland;

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115 Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, MA 02115 Departments of Medicine, Harvard Medical School, Boston, MA 02115;

    Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129 Departments of Medicine, Harvard Medical School, Boston, MA 02115;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    Mcl-1; MEK; BIM; acquired resistance; AKT;

    机译：Mcl-1;MEK;BIM;获得性抵抗AKT;

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