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首页> 外文期刊>Cancer Cell >AXL Mediates Resistance to PI3K alpha Inhibition by Activating the EGFR/PKC/mTOR Axis in Head and Neck and Esophageal Squamous Cell Carcinomas
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AXL Mediates Resistance to PI3K alpha Inhibition by Activating the EGFR/PKC/mTOR Axis in Head and Neck and Esophageal Squamous Cell Carcinomas

机译：AXL通过激活头颈部和食道鳞状细胞癌中的EGFR / PKC / mTOR轴介导对PI3Kα抑制的抗性

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摘要

Phosphoinositide-3-kinase (PI3K)-alpha inhibitors have shown clinical activity in squamous cell carcinomas (SCCs) of head and neck (H&N) bearing PIK3CA mutations or amplification. Studying models of therapeutic resistance, we have observed that SCC cells that become refractory to PI3K alpha inhibition maintain PI3K-independent activation of the mammalian target of rapamycin (mTOR). This persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. AXL is overexpressed in resistant tumors from both laboratory models and patients treated with the PI3K alpha inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase C gamma (PLC gamma)-protein kinase C (PKC), which, in turn, activates mTOR. Combined treatment with PI3K alpha and either EGFR, AXL, or PKC inhibitors reverts this resistance.
机译：Phosphoinositide-3-kinase（PI3K）-alpha抑制剂在具有PIK3CA突变或扩增的头颈部鳞状细胞癌（S＆s）中显示出临床活性。在研究治疗抗性模型时，我们已经观察到对PI3K alpha抑制变得难治的SCC细胞维持了雷帕霉素（mTOR）哺乳动物靶标的PI3K独立激活。这种持续的mTOR激活是由酪氨酸激酶受体AXL介导的。在实验室模型和接受PI3Kα抑制剂BYL719治疗的患者中，抗药性肿瘤中AXL均过表达。 AXL与表皮生长因子受体（EGFR）二聚并磷酸化，导致磷脂酶Cγ（PLCγ）-蛋白激酶C（PKC）激活，进而激活mTOR。 PI3Kα和EGFR，AXL或PKC抑制剂的联合治疗可恢复这种耐药性。

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