title: ANO1/TMEM16A interacts with EGFR and correlates with sensitivity to EGFR-targeting therapy in head and neck cancer.
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.
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Anke
authors.initials: A
authors.lastname: Bill
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Abraham
authors.initials: A
authors.lastname: Gutierrez
authors.affiliation: University of Pittsburgh, Medical Center, Department of Otolaryngology, Pittsburgh, PA 15213, USA.
authors.forename: Sucheta
authors.initials: S
authors.lastname: Kulkarni
authors.affiliation: University of Pittsburgh, Medical Center, Department of Otolaryngology, Pittsburgh, PA 15213, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Kemp
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, CH-4002, Switzerland.
authors.forename: Debora
authors.initials: D
authors.lastname: Bonenfant
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, CH-4002, Switzerland.
authors.forename: Hans
authors.initials: H
authors.lastname: Voshol
authors.affiliation: University of Pittsburgh, Medical Center, Department of Otolaryngology, Pittsburgh, PA 15213, USA.|VA Pittsburgh HealthCare System, Pittsburgh, PA 15213, USA.
authors.forename: Umamaheswar
authors.initials: U
authors.lastname: Duvvuri
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: L Alex
authors.initials: LA
authors.lastname: Gaither
mesh_terms: D000075369:Anoctamin-1; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics; D000077156:Gefitinib; D057809:HEK293 Cells; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; D018118:Chloride Channels; D027282:Fusion Regulatory Protein 1, Heavy Chain; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; C545989:SLC3A2 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: EGFR-targeted therapy; biomarker; calcium-activated chloride channel; epidermal growth factor receptor (EGFR); protein-protein interaction
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