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AXL Mediates Resistance to PI3Kα Inhibition by Activating the EGFR/PKC/mTOR Axis in Head and Neck and Esophageal Squamous Cell Carcinomas

2015; Cell Press; Volume: 27; Issue: 4 Linguagem: Inglês

10.1016/j.ccell.2015.03.010

1878-3686

Moshe Elkabets, Evangelos Pazarentzos, Dejan Juric, Qing Sheng, Raphael Pelossof, Samuel Brook, Ana Oaknin Benzaken, Jordi Rodón, Natasha Morse, Jenny Yan, Manway Liu, Rita Das, Yan Chen, Angela Tam, Huiqin Wang, Jinsheng Liang, Joseph M. Gurski, Darcy A. Kerr, Rafael Rosell, Cristina Teixidó, Alan Huang, Ronald Ghossein, Neal Rosen, Trever G. Bivona, Maurizio Scaltriti, José Baselga,

Pancreatic and Hepatic Oncology Research

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.