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Cancer Cell. 2015 Apr 13;27(4):533-46. 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.

Author information

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.

PMID:
25873175
PMCID:
PMC4398915
DOI:
10.1016/j.ccell.2015.03.010
[Indexed for MEDLINE]
Free PMC Article

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