biostudies-literatureWang JAmerican Cancer SocietyNIDCR NIH HHSNCI NIH HHSNIGMS NIH HHSNIH HHSNational Science Foundation486-495https://www.ebi.ac.uk/biostudies/studies/S-EPMC12797014biostudies-literatureUnknown48(2)<h4>Background</h4>Head and neck squamous cell carcinoma (HNSCC) is a malignancy with poor prognosis and survival. While epidermal growth factor receptor (EGFR) is a known driver of HNSCC, EGFR inhibitors show limited efficacy as monotherapies, suggesting that effective combination therapies are needed.<h4>Methods</h4>We performed GeCKO and Kinase CRISPR library screens to identify candidate knockouts that increase EGFR inhibitor sensitivity in resistant HNSCC cells. We validated a candidate using the CellTiter-Glo viability assay following RNA interference and investigated the mechanisms using apoptosis and cell cycle flow cytometry analysis.<h4>Results</h4>Kinase CRISPR library screens identified that PIK3C2A gene downregulation enhanced EGFR inhibitor sensitivity in resistant HNSCC cellHead & neckCRISPR Screens Identify PIK3C2A as a Novel Mediator of EGFR Inhibitor Resistance in Head and Neck Squamous Cell Carcinoma.PMC12797014F31 CA206341DGE-1256260R01 DE032699T32GM145470P30 CA046592F31 CA206341-03R01DE032699T32 GM145470P30-CA046592U01 DE025184U01DE025184Jiang HSwiecicki PWang JChinn SBBirkeland ACKulkarni ABuchakjian MHeft Neal MBrenner JCGensterblum-Miller ELudwig MLMichmerhuizen NLZhai JSpector MEfalseCRISPR Screens Identify PIK3C2A as a Novel Mediator of EGFR Inhibitor Resistance in Head and Neck Squamous Cell Carcinoma.<h4>Background</h4>Head and neck squamous cell carcinoma (HNSCC) is a malignancy with poor prognosis and survival. While epidermal growth factor receptor (EGFR) is a known driver of HNSCC, EGFR inhibitors show limited efficacy as monotherapies, suggesting that effective combination therapies are needed.<h4>Methods</h4>We performed GeCKO and Kinase CRISPR library screens to identify candidate knockouts that increase EGFR inhibitor sensitivity in resistant HNSCC cells. We validated a candidate using the CellTiter-Glo viability assay following RNA interference and investigated the mechanisms using apoptosis and cell cycle flow cytometry analysis.<h4>Results</h4>Kinase CRISPR library screens identified that PIK3C2A gene downregulation enhanced EGFR inhibitor sensitivity in resistant HNSCC cell2026-01-01T00:00:00Z2026 Feb2026-06-06T15:23:22.301Z2026-06-01T03:11:03.204ZS-EPMC127970144098504910.1002/hed.70048