biostudies-literatureBugide SNCI NIH HHSe2218118120https://www.ebi.ac.uk/biostudies/studies/S-EPMC9942844biostudies-literatureUnknown120(4)Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFRi) are approved for treating EGFR-mutant lung adenocarcinoma (LUAD), emergence of acquired resistance limits their clinical benefits. Several mechanisms for acquired resistance to EGFRi in LUAD have been identified; however, the molecular basis for this resistance remains unknown in ~30% of LUAD. Chromatin and DNA modifiers and their regulators play important roles in determining response to anticancer therapies. Therefore, to identify nongenetic mechanisms of EGFRi resistance in LUAD, we performed an epigenome-wide shRNA screen targeting 363 human epigenetic regulator genes. This screen identified loss of the transcriptional repressor chromobox homolog 5 (CBX5) as a driver of EGFRi resistance in EGFR-mutant LProceedings of the National Academy of Sciences of the United States of AmericaCBX5 loss drives EGFR inhibitor resistance and results in therapeutically actionable vulnerabilities in lung cancer.PMC9942844R01 CA257046R01 CA233481R03 CA248913R01 CA218008Gupta RWajapeyee NEdwards YJKGreen MRBugide SfalseCBX5 loss drives EGFR inhibitor resistance and results in therapeutically actionable vulnerabilities in lung cancer.Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFRi) are approved for treating EGFR-mutant lung adenocarcinoma (LUAD), emergence of acquired resistance limits their clinical benefits. Several mechanisms for acquired resistance to EGFRi in LUAD have been identified; however, the molecular basis for this resistance remains unknown in ~30% of LUAD. Chromatin and DNA modifiers and their regulators play important roles in determining response to anticancer therapies. Therefore, to identify nongenetic mechanisms of EGFRi resistance in LUAD, we performed an epigenome-wide shRNA screen targeting 363 human epigenetic regulator genes. This screen identified loss of the transcriptional repressor chromobox homolog 5 (CBX5) as a driver of EGFRi resistance in EGFR-mutant L2023-01-01T00:00:00Z2023 Jan2025-04-04T22:54:35.064Z2025-04-04T22:54:35.064ZS-EPMC99428443665247610.1073/pnas.2218118120