AXL Mediates Resistance to PI3Kα Inhibition by Activating the EGFR/PKC/mTOR Axis in Head and Neck and Esophageal Squamous Cell Carcinomas
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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.
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AXL inhibition sensitizes drug-resistant mesenchymal tumor cells to anticancer agents, including antimitotic agents, EGFR inhibitors, and PI3K inhibitors.
“AXL inhibition has been reported to sensitize drug-resistant mesenchymal tumor cells to anticancer agents, including antimitotic agents, epidermal growth factor receptor (EGFR) inhibitors, and PI3K inhibitors”
From Hypoxic control of metastasis (2016) · cites this paper as [85]
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- Authors
- Elkabets, M., Pazarentzos, E., Juric, D., Sheng, Q., Pelossof, R. A., Brook, S., Benzaken, A. O., Rodon, J., Morse, N., Yan, J. J., Liu, M., Das, R., Chen, Y., Tam, A., Wang, H., Liang, J., Gurski, J. M., Kerr, D. A., Rosell, R., Teixidó, C., Huang, A., Ghossein, R. A., Rosen, N., Bivona, T. G., Scaltriti, M., & Baselga, J.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of California, San Francisco (US)
- Massachusetts General Hospital (US)
- Vall d'Hebron Institute of Oncology (ES)
- Hospital Universitario Dexeus (ES)
- Corresponding author
- Scaltriti, Maurizio
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 27
- Issue
- 4
- Pages
- 533-546
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4398915
- OpenAlex
- W2039071845
- Cited by
- 325
- References
- 42
- Citations by year
- 2026: 4 · 2025: 18 · 2024: 31 · 2023: 27 · 2022: 36 · 2021: 28 · 2020: 36 · 2019: 34 · 2018: 31 · 2017: 29 · 2016: 41 · 2015: 8 · 2014: 1
- FWCI
- 15.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Memorial Sloan-Kettering Cancer Center
- Soochow University
- National Cancer Institute (R01CA169338, DP2CA174497, P30CA008748, K12CA087723, T32CA071345)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- AXL receptor tyrosine kinase, EGFR, protein kinase C, mTOR signaling, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, PIK3CA mutation, alpelisib, phospholipase C-gamma, combination therapy, treatment resistance
- MeSH terms
- Cetuximab, Esophageal Squamous Cell Carcinoma, Phosphoinositide-3 Kinase Inhibitors, Axl Receptor Tyrosine Kinase, Animals, Carcinoma, Squamous Cell, Esophageal Neoplasms, Head and Neck Neoplasms, Humans, Protein Kinase C, Proto-Oncogene Proteins, Thiazoles, Signal Transduction, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Receptor Protein-Tyrosine Kinases, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Class I Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases, Antibodies, Monoclonal, Humanized
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