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

Overview

MeSH Major

  • Carcinoma, Squamous Cell
  • Esophageal Neoplasms
  • Head and Neck Neoplasms
  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases

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.

publication date

  • January 2015

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4398915

Digital Object Identifier (DOI)

  • 10.1016/j.ccell.2015.03.010

PubMed ID

  • 25873175

Additional Document Info

start page

  • 533

end page

  • 46

volume

  • 27

number

  • 4