CDK4/6-targeted therapy: From clinical inhibitors to emerging strategies to overcome resistance.

The Cyclin-dependent kinase 4/6 (CDK4/6) complex orchestrates the critical G1-to-S phase transition by phosphorylating the Retinoblastoma protein (Rb), establishing it as a validated therapeutic target in oncology. The clinical deployment of ATP-competitive inhibitors-Palbociclib, Ribociclib, and Abemaciclib-has revolutionized the standard of care for hormone receptor-positive breast cancer. However, the long-term efficacy of these agents is inevitably compromised by the emergence of intrinsic and acquired resistance. This multifaceted resistance landscape is driven by genomic alterations including RB1 loss, activation of compensatory bypass signaling pathways, and the adaptive scaffolding functions of CDK6. Consequently, therapeutic strategies are evolving from simple inhibition to rational intervention. In this review, we systematically elucidate these emerging interventions. On one hand, we explore strategies grounded in the optimization of occupancy-based inhibition, specifically highlighting the synergistic combination regimens and rational design of dual-target small molecules to re-sensitize resistant tumors. On the other hand, we highlight the paradigm shift toward Proteolysis Targeting Chimera (PROTAC) technology. By recruiting the ubiquitin-proteasome system to catalytically degrade target proteins, CDK4/6-PROTACs eliminate both enzymatic activity and non-catalytic scaffolding functions, offering a mechanistically distinct strategy to overcome the structural limitations of traditional inhibitors. This review summarizes the progression from clinical inhibitors to strategies for overcoming resistance, offering insights into the future development of CDK4/6-targeted therapies.