Cell-cycle targeted cancer therapy: clinical advances, biological gaps, and the emergence of selective CDK4 inhibitors

Cyclin-dependent kinase (CDK) 4/6 inhibitors have reshaped the therapeutic landscape for hormone receptor (HR)-positive breast cancer and firmly established cell-cycle regulation as a viable target in oncology. Yet, despite strong biological rationale, their clinical impact outside this setting has expanded more slowly than anticipated. This review dissects key gaps in our understanding of CDK4/6-cyclin D signalling and its context-dependent roles in tumourigenesis. We begin by the outlining molecular biology of CDK4, CDK6, and D-type cyclins, highlighting their contributions to malignant proliferation and lineage-specific vulnerabilities. We then examine the therapeutic landscape defined by CDK4/6 inhibition, summarising key clinical successes as well as ongoing limitations, including resistance, restricted therapeutic applicability, and haematologic toxicities. Finally, we discuss emerging strategies to overcome these challenges, with particular emphasis on the development of next-generation, highly selective CDK4 inhibitors that may refine and extend the clinical utility of cell-cycle-targeted therapy.