Dataset Information

AXL mediates resistance to PI3K? inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas.

ABSTRACT: Phosphoinositide-3-kinase (PI3K)-? 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? 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? inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase C? (PLC?)-protein kinase C (PKC), which, in turn, activates mTOR. Combined treatment with PI3K? and either EGFR, AXL, or PKC inhibitors reverts this resistance.

SUBMITTER: Elkabets M

PROVIDER: S-EPMC4398915 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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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.

Elkabets Moshe M Pazarentzos Evangelos E Juric Dejan D Sheng Qing Q Pelossof Raphael A RA Brook Samuel S Benzaken Ana Oaknin AO Rodon Jordi J Morse Natasha N Yan Jenny Jiacheng JJ Liu Manway M Das Rita R Chen Yan Y Tam Angela A Wang Huiqin H Liang Jinsheng J Gurski Joseph M JM Kerr Darcy A DA Rosell Rafael R Teixidó Cristina C Huang Alan A Ghossein Ronald A RA Rosen Neal N Bivona Trever G TG Scaltriti Maurizio M Baselga José J

Cancer cell 20150401 4

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 fr ...[more]

PMID: 25873175

Dataset Information

AXL mediates resistance to PI3K? inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas.

Publications

AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas.

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