LAUSR

Oral squamous cell carcinoma (OSCC) is a disease with poor survival with few novel treatment options in development. While EGFR is commonly over-expressed, targeting EGFR has had limited success possibly because of compensatory pathways rescuing cell survival. Inhibiting compensatory pathways in combination with EGFR signaling may result in greater efficacy. To identify compensatory pathways, we used a Genome-wide CRISPR-Cas9 Knock-Out (GeCKO) library to identify genetic knockouts that sensitized OSCC cell lines to EGFR inhibition. This CRISPR library established a pool of knockouts targeting over 18,000 genes, and upon selection of the GeCKO pool we identified gene knockouts in the FGFR pathway increased sensitivity to the EGFR inhibitor gefitinib. We further profiled this combination with viability assays and found that 6/14 (43%) cell lines responded to the combination of EGFR and FGFR inhibition, suggesting that the FGFR pathway could be a common compensatory mechanism to loss of EGFR signaling. In complement, we again used CRISPR-Cas9 to generate a syngeneic EGFR knockout (KO) OSCC cell line. The parent OSCC cell line is responsive to the EGFR and FGFR dual inhibition, and the EGFR KO derivative retains sensitivity to FGFR-targeted monotherapies. We expect that this EGFR KO cell line will be a useful tool in further evaluating the compensatory mechanism of the FGFR pathway. In total, we describe the use of genome-wide CRISPR-Cas9 library to discover the synergistic combination of EGFR and FGFR inhibition, with follow-up indicating that the FGFR pathway could be a common compensatory mechanism to EGFR inhibition. Targeting compensatory mechanisms in combination with EGFR-targeted therapy could be clinically beneficial, including the combination of EGFR and FGFR inhibition. Citation Format: Megan Ludwig, Andrew Birkeland, Sai Nimmagadda, Sue Foltin, Aditi Kulkarni, Hui Jiang, Thomas Carey, J. Chad Brenner. Genome-wide CRISPR screen identifies potential therapeutic combination of EGFR and FGFR inhibitors in oral cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 54.