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 A Kerr; Rafael Rosell; Cristina Teixidó; Alan Huang; Ronald A Ghossein; Neal Rosen; Trever G Bivona; Maurizio Scaltriti; José Baselga

doi:10.1016/j.ccell.2015.03.010

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.

Authors

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

Affiliations

¹ Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
² Division of Hematology and Oncology, Department of Medicine, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA.
³ Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, USA.
⁴ Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
⁵ Computation Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
⁶ Medical Oncology, Vall d'Hebron Institute of Oncology, Pg Vall d'Hebron, 119-129, Barcelona 08035, Spain.
⁷ Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet s/n, 08916 Badalona, Spain; Pangaea Biotech SL, Laboratorio de Oncología, Hospital Universitario Quirón Dexeus, C/ Sabino Arana 5-19, 08028 Barcelona, Spain.
⁸ Pangaea Biotech SL, Laboratorio de Oncología, Hospital Universitario Quirón Dexeus, C/ Sabino Arana 5-19, 08028 Barcelona, Spain.
⁹ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁰ Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹¹ Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA. Electronic address: scaltrim@mskcc.org.
¹² Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA. Electronic address: baselgaj@mskcc.org.

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
Axl Receptor Tyrosine Kinase
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
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human
Receptor Protein-Tyrosine Kinases
TOR Serine-Threonine Kinases
Protein Kinase C
Cetuximab
Axl Receptor Tyrosine Kinase

Associated data

GEO/GSE61515

Abstract

MeSH terms

Substances

Associated data

Grants and funding