ANO1/TMEM16A interacts with EGFR and correlates with sensitivity to EGFR-targeting therapy in head and neck cancer
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Anke Bill1, Abraham Gutierrez1, Sucheta Kulkarni2, Carolyn Kemp2, Debora Bonenfant3, Hans Voshol3, Umamaheswar Duvvuri2,4,*, L. Alex Gaither1,*
1Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA
2University of Pittsburgh, Medical Center, Department of Otolaryngology, Pittsburgh, PA 15213, USA
3Novartis Institutes for Biomedical Research, Basel, CH-4002, Switzerland
4VA Pittsburgh HealthCare System, Pittsburgh, PA 15213, USA
*These authors have contributed equally to this work
L. Alex Gaither, e-mail: [email protected]
Umamaheswar Duvvuri, e-mail: [email protected]
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
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.
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