mTOR inhibition induces EGFR feedback activation in association with its resistance to human pancreatic cancer.
mTOR inhibition induces EGFR feedback activation in association with its resistance to human pancreatic cancer.
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mTOR 抑制可诱导 EGFR 反馈激活，并与其对人类胰腺癌的抵抗力相关。
DOI：
10.3390/ijms16023267
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发表时间：
2015-02-03
影响因子：
5.6
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Wei F;Zhang Y;Geng L;Zhang P;Wang G;Liu Y
哺乳动物的雷帕霉素靶点(MTOR)在多种癌症中调节失调，并与肿瘤的进展和耐药性有关。第一代mTOR抑制剂在治疗胰腺癌方面未能显示出临床疗效，部分原因是胰岛素样生长因子-1受体(IGF-1R)-AKT信号通路的反馈缓解。第二代mTOR抑制剂，如AZD8055，可通过抑制mTOR复合体2(MTORC2)而抑制AKT的激活。然而，这一代mTOR抑制剂在胰腺癌治疗中是否能获得令人满意的活性仍不清楚。在本研究中，我们发现AZD8055与依维莫司相比并没有太大的改善，AZD8055诱导了AKT活性的暂时抑制，然后AKT被重新磷酸化。此外，我们还发现，AZD8055诱导的瞬时AKT抑制通过释放其转录因子Fork-head box O 1/3a(FoxO1/3a)来增加表皮生长因子受体(EGFR)的表达和激活，这可能是导致细胞对AZD8055产生耐药性的原因之一。体外和体内实验进一步表明，AZD8055和厄洛替尼联合应用可协同抑制mTORC1/C2信号通路、EGFR/AKT反馈激活和细胞生长，并抑制胰腺癌的发展。这项研究为在胰腺癌治疗中联合应用EGFR抑制剂erlotinib来克服AZD8055耐药性提供了理论依据和策略。
The mammalian target of rapamycin (mTOR) is dysregulated in diverse cancers and contributes to tumor progression and drug resistance. The first generation of mTOR inhibitors have failed to show clinical efficiency in treating pancreatic cancers due in part to the feedback relief of the insulin-like growth factor-1 receptor (IGF-1R)-AKT signaling pathway. The second generation of mTOR inhibitors, such as AZD8055, could inhibit AKT activation upon mTOR complex 2 (mTORC2) inhibition. However, whether this generation of mTOR inhibitors can obtain satisfactory activities in pancreatic cancer therapy remains unclear. In this study, we found AZD8055 did not show great improvement compared with everolimus, AZD8055 induced a temporal inhibition of AKT kinase activities and AKT was then rephosphorylated. Additionally, we found that AZD8055-induced transient AKT inhibition increased the expression and activation of epidermal growth factor receptor (EGFR) by releasing its transcriptional factors Fork-head box O 1/3a (FoxO1/3a), which might contribute to cell resistance to AZD8055. The in vitro and in vivo experiments further indicated the combination of AZD8055 and erlotinib synergistically inhibited the mTORC1/C2 signaling pathway, EGFR/AKT feedback activation, and cell growth, as well as suppressed the progression of pancreatic cancer in a xenograft model. This study provides a rationale and strategy for overcoming AZD8055 resistance by a combined treatment with the EGFR inhibitor erlotinib in pancreatic cancer therapy.
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