title: AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas.
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.
authors: Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors: Moshe
authors: M
authors: Elkabets
authors: 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.
authors: Evangelos
authors: E
authors: Pazarentzos
authors: Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, USA.
authors: Dejan
authors: D
authors: Juric
authors: Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors: Qing
authors: Q
authors: Sheng
authors: Computation Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors: Raphael A
authors: RA
authors: Pelossof
authors: Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors: Samuel
authors: S
authors: Brook
authors: Medical Oncology, Vall d'Hebron Institute of Oncology, Pg Vall d'Hebron, 119-129, Barcelona 08035, Spain.
authors: Ana Oaknin
authors: AO
authors: Benzaken
authors: Medical Oncology, Vall d'Hebron Institute of Oncology, Pg Vall d'Hebron, 119-129, Barcelona 08035, Spain.
authors: Jordi
authors: J
authors: Rodon
authors: Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors: Natasha
authors: N
authors: Morse
authors: 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.
authors: Jenny Jiacheng
authors: JJ
authors: Yan
authors: Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors: Manway
authors: M
authors: Liu
authors: Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors: Rita
authors: R
authors: Das
authors: Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors: Yan
authors: Y
authors: Chen
authors: Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors: Angela
authors: A
authors: Tam
authors: Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors: Huiqin
authors: H
authors: Wang
authors: Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors: Jinsheng
authors: J
authors: Liang
authors: Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, USA.
authors: Joseph M
authors: JM
authors: Gurski
authors: Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, USA.
authors: Darcy A
authors: DA
authors: Kerr
authors: 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.
authors: Rafael
authors: R
authors: Rosell
authors: Pangaea Biotech SL, Laboratorio de Oncología, Hospital Universitario Quirón Dexeus, C/ Sabino Arana 5-19, 08028 Barcelona, Spain.
authors: Cristina
authors: C
authors: Teixidó
authors: Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors: Alan
authors: A
authors: Huang
authors: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Ronald A
authors: RA
authors: Ghossein
authors: 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.
authors: Neal
authors: N
authors: Rosen
authors: 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.
authors: Trever G
authors: TG
authors: Bivona
authors: 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.
authors: Maurizio
authors: M
authors: Scaltriti
authors: 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.
authors: José
authors: J
authors: Baselga
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000378:metabolism*; D000077277:Esophageal Squamous Cell Carcinoma; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D013844:Thiazoles; D000094963:Axl Receptor Tyrosine Kinase; C585539:Alpelisib; C546842:MTOR protein, human; C484760:PIK3CA protein, human