CBX5 Loss Drives EGFR Inhibitor Resistance and Results in Therapeutically Actionable Vulnerabilities in Lung Cancer

Authors

Suresh Bugide
Yvonne J K Edwards
Romi Gupta
Michael R Green
Narendra Wajapeyee

Publication Date

1-24-2023

Journal

Proceedings of the National Academy of Sciences of the United States of America

Abstract

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 LUAD. Loss of CBX5 confers resistance to multiple EGFRi in both cell culture and mice. We found that CBX5 loss in EGFR-mutant LUAD cells leads to increased expression of the transcription factor E2F1, which in turn stimulates expression of the antiapoptotic gene

Keywords

Humans, Animals, Mice, Lung Neoplasms, ErbB Receptors, Adenocarcinoma of Lung, RNA, Small Interfering, Drug Resistance, Neoplasm, Cell Line, Tumor

Comments

Supplementary Materials

PMID: 36652476