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

Cancer Cell. 2015 Apr 13;27(4):533-46. doi: 10.1016/j.ccell.2015.03.010.

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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Carcinoma, Squamous Cell / metabolism*
  • Cell Line, Tumor
  • Cetuximab
  • Class I Phosphatidylinositol 3-Kinases
  • Drug Resistance, Neoplasm
  • Esophageal Neoplasms / metabolism*
  • Esophageal Squamous Cell Carcinoma
  • Head and Neck Neoplasms / metabolism*
  • Humans
  • Mice
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase C / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Thiazoles / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal, Humanized
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Thiazoles
  • Alpelisib
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase
  • Protein Kinase C
  • Cetuximab

Associated data

  • GEO/GSE61515