ANO1/TMEM16A interacts with EGFR and correlates with sensitivity to EGFR-targeting therapy in head and neck cancer
| Autor: | Sucheta Kulkarni, Debora Bonenfant, Carolyn Kemp, Hans Voshol, Abraham Gutierrez, Anke Bill, Umamaheswar Duvvuri, L. Alex Gaither |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Fusion Regulatory Protein 1
Heavy Chain medicine.medical_treatment EGFR-targeted therapy Targeted therapy protein-protein interaction Pathogenesis Gefitinib stomatognathic system Chloride Channels Cell Line Tumor otorhinolaryngologic diseases medicine Humans Epidermal growth factor receptor RNA Small Interfering neoplasms Protein Kinase Inhibitors Anoctamin-1 Cell Proliferation Predictive marker biology Squamous Cell Carcinoma of Head and Neck Cell growth calcium-activated chloride channel Head and neck cancer medicine.disease epidermal growth factor receptor (EGFR) Neoplasm Proteins Protein Structure Tertiary ErbB Receptors stomatognathic diseases HEK293 Cells Oncology Head and Neck Neoplasms Multiprotein Complexes Mutation Carcinoma Squamous Cell Quinazolines Cancer research biology.protein biomarker Biomarker (medicine) RNA Interference Research Paper Signal Transduction medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.3277 |
| Popis: | // Anke Bill 1 , Abraham Gutierrez 1 , Sucheta Kulkarni 2 , Carolyn Kemp 2 , Debora Bonenfant 3 , Hans Voshol 3 , Umamaheswar Duvvuri 2, 4, * , L. Alex Gaither 1, * 1 Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA 2 University of Pittsburgh, Medical Center, Department of Otolaryngology, Pittsburgh, PA 15213, USA 3 Novartis Institutes for Biomedical Research, Basel, CH-4002, Switzerland 4 VA Pittsburgh HealthCare System, Pittsburgh, PA 15213, USA * These authors have contributed equally to this work Correspondence to: L. Alex Gaither, e-mail: alex.gaither@novartis.com Umamaheswar Duvvuri, e-mail: duvvuriu@upmc.edu Keywords: epidermal growth factor receptor (EGFR), EGFR-targeted therapy, biomarker, calcium-activated chloride channel, protein-protein interaction Received: December 01, 2014 Accepted: February 07, 2015 Published: March 16, 2015 ABSTRACT The epidermal growth factor receptor (EGFR) contributes to the pathogenesis of head&neck squamous cell carcinoma (HNSCC). However, only a subset of HNSCC patients benefit from anti-EGFR targeted therapy. By performing an unbiased proteomics screen, we found that the calcium-activated chloride channel ANO1 interacts with EGFR and facilitates EGFR-signaling in HNSCC. Using structural mutants of EGFR and ANO1 we identified the trans/juxtamembrane domain of EGFR to be critical for the interaction with ANO1. Our results show that ANO1 and EGFR form a functional complex that jointly regulates HNSCC cell proliferation. Expression of ANO1 affected EGFR stability, while EGFR-signaling elevated ANO1 protein levels, establishing a functional and regulatory link between ANO1 and EGFR. Co-inhibition of EGFR and ANO1 had an additive effect on HNSCC cell proliferation, suggesting that co-targeting of ANO1 and EGFR could enhance the clinical potential of EGFR-targeted therapy in HNSCC and might circumvent the development of resistance to single agent therapy. HNSCC cell lines with amplification and high expression of ANO1 showed enhanced sensitivity to Gefitinib, suggesting ANO1 overexpression as a predictive marker for the response to EGFR-targeting agents in HNSCC therapy. Taken together, our results introduce ANO1 as a promising target and/or biomarker for EGFR-directed therapy in HNSCC. |
| Databáze: | OpenAIRE |
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