This review explores strategies to overcome the clinical limitations of Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, namely, reversible cytostasis and acquired resistance. We outline an emerging therapeutic framework in which these inhibitors induce specific vulnerabilities, shifting the treatment objective from growth suppression toward tumor clearance. Specifically, we analyze the effects of CDK4/6 inhibitors across four interconnected domains: cellular senescence, compromised DNA damage repair, metabolic reprogramming, and immune microenvironment remodeling. Building upon this framework, we summarize rational combination strategies─such as pairing with senolytics, poly(ADP-ribose) polymerase (PARP) inhibitors, or immune checkpoint inhibitors (ICIs)─designed to exploit these induced vulnerabilities. To bridge preclinical rationale with clinical application, we discuss key translational determinants, noting that successful implementation depends on biomarker-guided patient selection and optimized dosing schedules (e.g., sequential administration) to mitigate overlapping toxicities. Collectively, the evidence suggests that rational combination strategies could repurpose CDK4/6 inhibitor therapy for more durable tumor control.
Ma et al. (Wed,) studied this question.