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

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

Research output: Contribution to journalArticle

138 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)533-546
Number of pages14
JournalCancer Cell
Volume27
Issue number4
DOIs
StatePublished - Apr 13 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Elkabets, M., Pazarentzos, E., Juric, D., Sheng, Q., Pelossof, R. A., Brook, S., Benzaken, A. O., Rodon, J., Morse, N., Yan, J. J., Liu, M., Das, R., Chen, Y., Tam, A., Wang, H., Liang, J., Gurski, J. M., Kerr, D., Rosell, R., ... Baselga, J. (2015). AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR Axis in Head and neck and esophageal squamous cell carcinomas. Cancer Cell, 27(4), 533-546. https://doi.org/10.1016/j.ccell.2015.03.010