ArticleCancer cell2015
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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Article in Cancer cell, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 200 papers.
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200citing papers in PubMed
16.3field-weighted citation impact, top 1% of its field
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Who cites it
200 citing papers in PubMed, 338 citations in OpenAlex.
- A Phase 1b/2 Study of Alpelisib in Combination with Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.Targeted oncology · 2023Trial
- Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial.The Lancet. Oncology · 2017Trial
- Feasibility of Targeting PIK3CA Mutations in Head and Neck Squamous Cell Carcinoma.Pathology oncology research : POR · 2016Trial
- AXL at the nexus of therapeutic resistance, tumor vascularization, and immune evasion in cancer.iScience · 2026Review
- AXL phosphosite mapping links FAK1 and YAP1 signaling to erlotinib resistance in EGFR-mutant lung cancer.Cell reports · 2026Article
- A Convergence Model of Bioelectric, Gap Junctional, and Hippo-YAP Signalling in Oral Cancer Stem Cell Maintenance.International journal of molecular sciences · 2026Review
- AXL is a novel ERK5/KLF4 target in MEK inhibitor-treated melanoma.Neoplasia (New York, N.Y.) · 2026Article
- Targeting FGFR signaling overcomes therapeutic resistance and immune evasion in oncogenic PIK3CA-driven serous-like endometrial cancer.Nature communications · 2026Article
- CRISPR Screens Identify PIK3C2A as a Novel Mediator of EGFR Inhibitor Resistance in Head and Neck Squamous Cell Carcinoma.Head & neck · 2026Article
- Synergistic Anticancer Effects of Lenvatinib Combined with N-butylidenephthalide in Human Colorectal Cancer Cells.International journal of medical sciences · 2026Article
- ZDHHC11-mediated AXL palmitoylation promotes osimertinib resistance in non-small-cell lung cancer.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Life Factors and Melanoma: From the Macroscopic State to the Molecular Mechanism.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- In Silico Discovery of a Novel Natural Product Targeting PI3Kα for the Treatment of Head and Neck Squamous Cell Carcinoma.International journal of molecular sciences · 2025Article
- Carotenoids Modulate FoxO-Induced Cell Cycle Awrrest in Human Cancer Cell Lines: A Scoping Review.Food science & nutrition · 2025Article
- Fatty acid uptake activates an AXL-CAV1-β-catenin axis to drive melanoma progression.Genes & development · 2025Article
- Navigating TAM receptor dynamics in tumour immunotherapy.Cancer immunology, immunotherapy : CII · 2025Review
- Proteolysis of TAM receptors in autoimmune diseases and cancer: what does it say to us?Cell death & disease · 2025Review
- AXL signaling in cancer: from molecular insights to targeted therapies.Signal transduction and targeted therapy · 2025Review
- AXL: shapers of tumor progression and immunosuppressive microenvironments.Molecular cancer · 2025Review
- YAP-driven malignant reprogramming of oral epithelial stem cells at single cell resolution.Nature communications · 2025Article
140 more citing papers are in PubMed but not listed here.
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Authors and funding
26 authors at 5 institutions in 2 countries.
Moshe ElkabetsHuman Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
Evangelos PazarentzosDivision 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.
Dejan JuricMassachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, USA.
Qing ShengOncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
Raphael A PelossofComputation Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
Samuel BrookHuman Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
Ana Oaknin BenzakenMedical Oncology, Vall d'Hebron Institute of Oncology, Pg Vall d'Hebron, 119-129, Barcelona 08035, Spain.
Jordi RodonMedical Oncology, Vall d'Hebron Institute of Oncology, Pg Vall d'Hebron, 119-129, Barcelona 08035, Spain.
Natasha MorseHuman Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
Jenny Jiacheng YanDivision 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.
Manway LiuOncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
Rita DasOncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
Yan ChenOncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
Angela TamOncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
Huiqin WangOncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
Jinsheng LiangOncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
Joseph M GurskiMassachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, USA.
Darcy A KerrMassachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, USA.
Rafael RosellCatalan 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.
Cristina TeixidóPangaea Biotech SL, Laboratorio de Oncología, Hospital Universitario Quirón Dexeus, C/ Sabino Arana 5-19, 08028 Barcelona, Spain.
Alan HuangOncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
Ronald A GhosseinDepartment of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Neal RosenHuman 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.
Trever G BivonaDivision 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.
Maurizio ScaltritiHuman Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA. Electronic address: scaltrim@mskcc.org.
José BaselgaHuman 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.
Memorial Sloan Kettering Cancer Center · USMassachusetts General Hospital · USUniversity of California, San Francisco · USHospital Universitario Dexeus · ESVall d'Hebron Hospital Universitari · ES
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Nicholas D Socci · 1985 to 2026
$347.4MDana Farber/Harvard Cancer Consortium Career Development Program in Clinical OncologyK12CA087723 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI David Tsai Ting · 2002 to 2026
$17.9MTraining Program in Cancer Biology and TherapeuticsT32CA071345 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Daniel A. Haber, Lecia V. Sequist · 1997 to 2026
$10.6MRational Combined Inhibition of NF-kB and EGFR to Optimize Lung Cancer TreatmentR01CA169338 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BIVONA, TREVER G · 2013 to 2023
$3.4MDiscovery of Rational Companion Therapeutic Targets to Optimize Cancer TreatmentDP2CA174497 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BIVONA, TREVER G · 2012 to 2012
$2.3MNCI NIH HHS DP2 CA174497NCI NIH HHS K12 CA087723NCI NIH HHS P30 CA008748NCI NIH HHS R01 CA169338NCI NIH HHS T32 CA071345
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.
Indexed as
AnimalsAntibodies, Monoclonal, HumanizedAxl Receptor Tyrosine KinaseCarcinoma, Squamous CellCell Line, TumorCetuximabClass I Phosphatidylinositol 3-KinasesDrug Resistance, NeoplasmEsophageal NeoplasmsEsophageal Squamous Cell CarcinomaHead and Neck NeoplasmsHumansMicePhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein Kinase CAlpelisibAntibodies, Monoclonal, HumanizedAxl Receptor Tyrosine KinaseCetuximabClass I Phosphatidylinositol 3-KinasesMTOR protein, humanPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsPIK3CA protein, humanProtein Kinase CProtein Kinase InhibitorsProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesThiazolesTOR Serine-Threonine Kinases
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