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Cotargeting CDK4/6 and BRD4 Promotes Senescence and Ferroptosis Sensitivity in Cancer
Xianbing Zhu1,2, Zheng Fu1,2, Kendall Dutchak3
1Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
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.
Significance:
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.
Insights
Combining CDK4/6 and BRD4 inhibitors induces cancer cell senescence, making them vulnerable to ferroptosis via GPX4 targeting. This strategy enhances cancer treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are established treatments for breast cancer and show promise in other cancers like KRAS-mutant non-small cell lung cancer (NSCLC).
- Clinical use of CDK4/6 inhibitors is often limited by drug resistance and primarily cytostatic effects, necessitating novel therapeutic strategies.
Purpose of the Study:
- To identify mechanisms of resistance to CDK4/6 inhibitors and explore combination therapies to overcome these limitations.
- To investigate the role of bromodomain-containing protein 4 (BRD4) in CDK4/6 inhibitor resistance and its potential as a therapeutic target.
Main Methods:
- Genome-wide cDNA screening to identify resistance factors to palbociclib in KRAS-mutant NSCLC cells.
- Inhibition of BRD4 using RNA interference and small-molecule inhibitors in combination with palbociclib.
- Assessment of cellular senescence, reactive oxygen species (ROS) accumulation, GPX4 expression, and ferroptosis induction.
- Evaluation of therapeutic efficacy in KRAS-mutant NSCLC mouse models and other cancer cell lines (pancreatic, breast).
Main Results:
- BRD4 overexpression was identified as a mechanism conferring resistance to palbociclib in KRAS-mutant NSCLC.
- Combined inhibition of CDK4/6 and BRD4 synergistically induced senescence and prolonged survival in a preclinical NSCLC model.
- BRD4 inhibition enhanced cell-cycle arrest, ROS accumulation, and increased vulnerability to ferroptosis by modulating GPX4 levels.
- This combination strategy demonstrated efficacy in pancreatic and breast cancer cells, suggesting broader applicability.
Conclusions:
- Co-targeting CDK4/6 and BRD4 represents a promising strategy to overcome resistance and enhance the efficacy of CDK4/6 inhibitors.
- The combination induces senescent cancer cells that are susceptible to ferroptosis, offering a novel therapeutic approach.
- Targeting GPX4 in combination with CDK4/6 and BRD4 inhibitors can lead to tumor regression and improved survival outcomes.
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