Elkabets Moshe, Pazarentzos Evangelos, Juric Dejan, Sheng Qing, Pelossof Raphael A, Brook Samuel, Benzaken Ana Oaknin, Rodon Jordi, Morse Natasha, Yan Jenny Jiacheng, Liu Manway, Das Rita, Chen Yan, Tam Angela, Wang Huiqin, Liang Jinsheng, Gurski Joseph M, Kerr Darcy A, Rosell Rafael, Teixidó Cristina, Huang Alan, Ghossein Ronald A, Rosen Neal, Bivona Trever G, Scaltriti Maurizio, Baselga José
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
Division of Hematology and Oncology, Department of Medicine, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA.
Cancer Cell. 2015 Apr 13;27(4):533-46. doi: 10.1016/j.ccell.2015.03.010.
Phosphoinositide-3-kinase (PI3K)-α 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 PI3Kα 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 PI3Kα inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase Cγ (PLCγ)-protein kinase C (PKC), which, in turn, activates mTOR. Combined treatment with PI3Kα and either EGFR, AXL, or PKC inhibitors reverts this resistance.
磷脂酰肌醇-3-激酶（PI3K）-α抑制剂已在携带PIK3CA突变或扩增的头颈部鳞状细胞癌（H&N SCC）中显示出临床活性。在研究治疗耐药模型时，我们观察到对PI3Kα抑制产生耐药的SCC细胞维持雷帕霉素哺乳动物靶标（mTOR）的PI3K非依赖性激活。这种持续的mTOR激活由酪氨酸激酶受体AXL介导。AXL在实验室模型和接受PI3Kα抑制剂BYL719治疗的患者的耐药肿瘤中均过表达。AXL与表皮生长因子受体（EGFR）二聚化并使其磷酸化，导致磷脂酶Cγ（PLCγ）-蛋白激酶C（PKC）激活，进而激活mTOR。PI3Kα与EGFR、AXL或PKC抑制剂联合治疗可逆转这种耐药性。
