CBX5 loss drives EGFR inhibitor resistance and results in therapeutically actionable vulnerabilities in lung cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS 2023-01, Vol.120 (4), p.e2218118120-e2218118120
• Main Authors: Bugide, Suresh, Edwards, Yvonne J K, Gupta, Romi, Green, Michael R, Wajapeyee, Narendra
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma of Lung - drug therapy; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - pathology; Animals; Apoptosis; Biological Sciences; Cell culture; Cell Line, Tumor; Chromatin; Drug Resistance, Neoplasm - genetics; Epidermal growth factor; Epidermal growth factor receptors; Epigenetics; ErbB Receptors - metabolism; Gene expression; Growth factors; Humans; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mice; Mutants; Protein-tyrosine kinase; RNA, Small Interfering - genetics; RNA, Small Interfering - therapeutic use; Survivin; Tyrosine
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2218118120

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 ( ). This E2F1-mediated upregulation of BIRC5 in -knockdown LUAD cells attenuates apoptosis induction following EGFRi treatment. Consistent with these results, knockdown of or partly rescues -knockdown-induced EGFRi resistance in cell culture and mice. EGFRi-resistant LUAD cell lines show reduced CBX5 expression compared to parental lines; however, bromo- and extra-terminal (BET)-domain inhibitors (BETi) restore CBX5 expression in these cells and sensitize them to EGFRi/BETi combination therapy. Similarly, treatment with a BIRC5 inhibitor suppresses growth of EGFRi-resistant LUAD cells. Collectively, these studies identify CBX5 loss as a driver of EGFRi resistance and reveal therapeutic opportunities for treating EGFRi-resistant LUAD.