American Association for Cancer Research
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can-23-1749_supplementary_data_suppsd.pdf (9.32 MB)

Supplementary Data from Cotargeting CDK4/6 and BRD4 Promotes Senescence and Ferroptosis Sensitivity in Cancer

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journal contribution
posted on 2024-04-15, 18:21 authored by Xianbing Zhu, Zheng Fu, Kendall Dutchak, Azadeh Arabzadeh, Simon Milette, Jutta Steinberger, Geneviève Morin, Anie Monast, Virginie Pilon, Tim Kong, Bianca N. Adams, Erika Prando Munhoz, Hannah J.B. Hosein, Tianxu Fang, Jing Su, Yibo Xue, Roni Rayes, Veena Sangwan, Logan A. Walsh, Guojun Chen, Daniela F. Quail, Jonathan D. Spicer, Morag Park, David Dankort, Sidong Huang

List of supplementary data and Supplementary Figures 1-9.

Funding

Canadian Institutes of Health Research (IRSC)

History

ARTICLE ABSTRACT

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for breast cancer treatment and show activity against other malignancies, including KRAS-mutant non–small cell lung cancer (NSCLC). However, the clinical efficacy of CDK4/6 inhibitors is limited due to frequent drug resistance and their largely cytostatic effects. Through a genome-wide cDNA screen, we identified that bromodomain-containing protein 4 (BRD4) overexpression conferred resistance to the CDK4/6 inhibitor palbociclib in KRAS-mutant NSCLC cells. Inhibition of BRD4, either by RNA interference or small-molecule inhibitors, synergized with palbociclib to induce senescence in NSCLC cells and tumors, and the combination prolonged survival in a KRAS-mutant NSCLC mouse model. Mechanistically, BRD4-inhibition enhanced cell-cycle arrest and reactive oxygen species (ROS) accumulation, both of which are necessary for senescence induction; this in turn elevated GPX4, a peroxidase that suppresses ROS-triggered ferroptosis. Consequently, GPX4 inhibitor treatment selectively induced ferroptotic cell death in the senescent cancer cells, resulting in tumor regression. Cotargeting CDK4/6 and BRD4 also promoted senescence and ferroptosis vulnerability in pancreatic and breast cancer cells. Together, these findings reveal therapeutic vulnerabilities and effective combinations to enhance the clinical utility of CDK4/6 inhibitors. The combination of cytostatic CDK4/6 and BRD4 inhibitors induces senescent cancer cells that are primed for activation of ferroptotic cell death by targeting GPX4, providing an effective strategy for treating cancer.