TY - JOUR T1 - Functional RNAi Screens Define Distinct Protein Kinase Vulnerabilities in EGFR-Dependent HNSCC Cell Lines JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.119.117804 SP - mol.119.117804 AU - Trista K. Hinz AU - Emily K. Kleczko AU - Katherine R. Singleton AU - Jacob Calhoun AU - Lindsay A. Marek AU - Jihye Kim AU - Aik-Choon Tan AU - Lynn E. Heasley Y1 - 2019/01/01 UR - http://molpharm.aspetjournals.org/content/early/2019/09/25/mol.119.117804.abstract N2 - The inhibitory epidermal growth factor receptor (EGFR) antibody, cetuximab, is an approved therapy for head and neck squamous cell carcinoma (HNSCC). Despite tumor response observed in some HNSCC patients, cetuximab alone or combined with radio- or chemotherapy fails to yield long-term control or cures. We hypothesize that a flexible receptor tyrosine kinase co-activation signaling network supports HNSCC survival in the setting of EGFR blockade and that drugs disrupting this network will provide superior tumor control when combined with EGFR inhibitors. Herein, we submitted EGFR-dependent HNSCC cell lines to RNAi-based functional genomics screens to identify, in an unbiased fashion, essential protein kinases for growth and survival as well as synthetic lethal targets for combined inhibition with EGFR inhibitors. MTOR and ERBB3 were identified as high-ranking essential kinase hits in the HNSCC cell lines. MTOR dependency was confirmed by distinct shRNAs and high sensitivity of the cell lines to AZD8055 while ERBB3 dependency was validated by shRNA-mediated silencing. Further, a synthetic lethal kinome shRNA screen with a pan-ERBB inhibitor, AZD8931, identified multiple components of the ERK MAPK pathway, consistent with ERK reactivation and/or incomplete ERK pathway inhibition in response to EGFR inhibitor monotherapy. As validation, distinct MEK inhibitors yielded synergistic growth inhibition when combined with the EGFR inhibitors, gefitinib and AZD8931. The findings identify ERBB3 and MTOR as important pharmacological vulnerabilities in HNSCC and support combining MEK and EGFR inhibitors to enhance clinical efficacy in HNSCC.SIGNIFICANCE STATEMENT Many cancers are driven by non-mutated receptor tyrosine kinase co-activation networks that defy full inhibition with single targeted drugs. This study identifies ERBB3 as an essential protein kinase in EGFR-dependent HNSCC cell lines and a synthetic lethal interaction with the ERK MAPK pathway that provides a rationale for combining pan-ERBB and MAPK inhibitors as a therapeutic approach in subsets of HNSCC. ER -