Next-Generation CDK Inhibitors in Breast Cancer: Expanding the Therapeutic Landscape Beyond CDK4/6 inhibitors

Background:The efficacy of CDK4/6 inhibitors in hormone receptor-positive (HR+) breast cancer has catalyzed the exploration of other cyclin-dependent kinases (CDKs) as therapeutic targets. Numerous CDK family members are aberrantly activated in breast cancer, driving disease progression via both cell cycle-dependent and independent mechanisms, while unmet clinical needs persist in overcoming therapy resistance and treating aggressive subtypes. Summary:This review synthesizes current knowledge on the pathological roles of key CDKs (CDK1, 2, 5, 7, 8, 9, 12) in breast cancer, emphasizing their functions in promoting proliferation, metastasis, and resistance to chemotherapy, anti-HER2 agents, and CDK4/6 inhibitors. We provide a systematic update on the de-velopment and clinical trial progress of novel CDK inhibitors targeting these resistance mechanisms, and examine innovative applications including combinations with im-munotherapies and rational design of CDK inhibitor-based antibody-drug conjugates (ADCs). Key Messages:Targeting a broader spectrum of CDKs represents a viable and promising strategy to address unmet clinical needs in breast cancer. The expanding landscape of CDK-targeted therapies—both as single agents and rational combina-tions—is poised to significantly reshape future treatment paradigms, particularly for overcoming therapy resistance and managing aggressive subtypes.