MAPK1E322K mutation increases head and neck squamous cell carcinoma sensitivity to erlotinib through enhanced secretion of amphiregulin

Abstract

// Yihui Wen 1,2,* , Hua Li 3,* , Yan Zeng 3 , Weiping Wen 1 , Kelsey P. Pendleton 2 , Vivian W.Y. Lui 4 , Ann Marie Egloff 2,5,** and Jennifer R. Grandis 3,6,** 1 Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China 2 Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA 3 Department of Otolaryngology Head and Neck Surgery, University of California at San Francisco, San Francisco, California, USA 4 Department of Pharmacology and Pharmacy, School of Biomedical Sciences, Li-Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR 5 Departments of Molecular and Cell Biology and Otolaryngology, Boston University, Boston, Massachusetts, USA 6 Clinical and Translational Science Institute, University of California at San Francisco, San Francisco, California, USA * Authors contributed equally to this work as first author ** Authors contributed equally to this work as last author Correspondence to: Ann Marie Egloff, email: // Keywords : head and neck cancer, MAPK1, ERK2, mutation, amphiregulin Received : March 02, 2016 Accepted : March 06, 2016 Published : March 18, 2016 Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have not been effective in unselected head and neck squamous cell carcinoma (HNSCC) populations. We previously reported an exceptional response to a brief course of erlotinib in a patient with advanced HNSCC whose tumor harbored a MAPK1 E322K somatic mutation. MAPK1 E322K was associated with increased p-EGFR, increased EGFR downstream signaling and increased sensitivity to erlotinib. In this study, we investigated the mechanism of MAPK1 E322K - mediated EGFR activation in the context of erlotinib sensitivity. We demonstrated increased AREG secretion in HNSCC cell lines harboring endogenous or exogenous MAPK1 E322K compared to wild type MAPK1 . We found inhibition or knockdown of MAPK1 with siRNA resulted in reduced secretion of AREG and decreased sensitivity to erlotinib in the setting of MAPK1 E322K . MAPK1 E322K was associated with increased AREG secretion leading to an autocrine feedback loop involving AREG, EGFR and downstream signaling. Knockdown of AREG in HNSCC cells harboring MAPK1 E322K abrogated EGFR signaling and decreased sensitivity to erlotinib in vitro and in vivo . These cumulative findings implicate increased AREG secretion and EGFR activation as contributing to increased erlotinib sensitivity in MAPK1 E322K HNSCC.