title: MAPK1E322K mutation increases head and neck squamous cell carcinoma sensitivity to erlotinib through enhanced secretion of amphiregulin.
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 MAPK1E322K somatic mutation. MAPK1E322Kwas associated with increased p-EGFR, increased EGFR downstream signaling and increased sensitivity to erlotinib. In this study, we investigated the mechanism of MAPK1E322K-mediated EGFR activation in the context of erlotinib sensitivity. We demonstrated increased AREG secretion in HNSCC cell lines harboring endogenous or exogenous MAPK1E322K 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 MAPK1E322K. MAPK1E322K 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 MAPK1E322K 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 MAPK1E322K HNSCC.
authors.affiliation: Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China.|Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Yihui
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, University of California at San Francisco, San Francisco, California, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, University of California at San Francisco, San Francisco, California, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Wen
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Kelsey P
authors.initials: KP
authors.lastname: Pendleton
authors.affiliation: 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.
authors.forename: Vivian W Y
authors.initials: VW
authors.lastname: Lui
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.|Departments of Molecular and Cell Biology and Otolaryngology, Boston University, Boston, Massachusetts, USA.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Egloff
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, University of California at San Francisco, San Francisco, California, USA.|Clinical and Translational Science Institute, University of California at San Francisco, San Francisco, California, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
mesh_terms: D066258:Amphiregulin / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics*; D009154:Mutation; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D066258:Amphiregulin; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000069347:Erlotinib Hydrochloride; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1
keywords: ERK2; MAPK1; amphiregulin; head and neck cancer; mutation