Abstract B27: Identifying therapeutic combinations with EGFR-targeted therapy through the generation of genome-wide CRISPR-Cas9 knockout libraries in oral cancer cell lines

Oral squamous cell carcinoma (OSCC) remains a disease with poor survival. With recent characterization of the mutational landscape of OSCCs, there is great potential for personalized targeted therapies. However, to date utilization of targeted therapies in OSCC have had limited success with anti-EGFR therapy. Combinations of targeted therapies, which may have greater efficacy by inhibiting compensatory pathways, have not been well studied. To identify synergistic combinations with EGFR-targeted therapy, we introduced Genome-scale CRISPR-Cas9 Knock-Out (GeCKO) libraries into OSCC cell lines. CRISPR-Cas9 generates individual genetic knockouts through targeted gene editing, and by using a pool of CRISPRs targeting over 18,000 genes we can perform genome-scale screening for synergistic targetable pathways. Upon selection of the OSCC GeCKO pool, we identified that knockouts of genes in the FGFR pathway caused sensitivity to the EGFR inhibitor gefitinib. We further investigated the possible synergistic effect of dual EGFR and FGFR inhibition with resazurin viability assays in 14 of our OSCC models. We found 6/14 (43%) of the models were responsive to the combination of EGFR and FGFR inhibition, indicating that the FGFR pathway could be an alternate mechanism of resistance to EGFR-targeted therapy. For further investigation of this combination, we again used CRISPR-Cas9 to generate an EGFR knockout (KO) OSCC cell line. This EGFR KO cell line retains sensitivity to FGFR inhibitors, a...
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Tags: Resistance Against Drug Combinations: Poster Presentations - Proffered Abstracts Source Type: research