Abstract
Oncogenic alterations in fibroblast growth factor receptor (FGFR) are frequent, but therapeutic targeting of FGFR-driven cancers remains an unmet challenge in clinical oncology in that FGFR inhibitors as a single agent are inevitably limited by poor responsiveness and/or compensatory activation of various acquired resistance mechanisms. We performed kinome CRISPR/Cas9 screens to identify genetic determinants that limit efficacy of FGFR-targeted therapy in FGFR-mutant squamous lung carcinoma (SQLC). We identify several kinases including polo-like kinase I (PLK1) as key determinants of sensitivity to AZD4547, a selective FGFR inhibitor currently investigated in phase III clinical trials. We provided evidence showing that genetic and pharmacological inhibition of PLK1 synergistically enhances the effect of FGFR inhibitors in FGFR-amplified lung SQLC. CRISPR/Cas9 screening is a powerful tool to uncover genetic determinants underlying drug sensitivity in cancer.
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