| Literature DB >> 25873175 |
Moshe Elkabets1, Evangelos Pazarentzos2, Dejan Juric3, Qing Sheng4, Raphael A Pelossof5, Samuel Brook1, Ana Oaknin Benzaken6, Jordi Rodon6, Natasha Morse1, Jenny Jiacheng Yan2, Manway Liu4, Rita Das4, Yan Chen4, Angela Tam4, Huiqin Wang4, Jinsheng Liang4, Joseph M Gurski3, Darcy A Kerr3, Rafael Rosell7, Cristina Teixidó8, Alan Huang4, Ronald A Ghossein9, Neal Rosen10, Trever G Bivona2, Maurizio Scaltriti11, José Baselga12.
Abstract
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.Entities:
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Year: 2015 PMID： 25873175 PMCID： PMC4398915 DOI： 10.1016/j.ccell.2015.03.010
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743