Is it feasible for CDKs inhibitors to herald a new era in tackling the low sensitivity and drug resistance associated with PARP inhibitors?

PARPi exerts synthetic lethality by exploiting homologous recombination repair (HRR) deficiencies in tumor cells, demonstrating breakthrough efficacy in the treatment of various cancers with BRCA mutations, and has thus become one of the cornerstone strategies in precision oncology. However, primary insensitivity and acquired resistance observed in clinical practice significantly limit its long-term therapeutic benefits. Cyclin-dependent kinases (CDKs), as critical regulators of cell cycle progression and DNA damage repair pathways, represent promising therapeutic targets for overcoming PARPi resistance and enhancing treatment sensitivity. Through modulation of HRR-related gene transcription, activation of cell cycle checkpoints, and regulation of pro-survival signaling pathways in tumors, CDKs play a pivotal role in mediating these effects.This article systematically reviews the core mechanisms underlying the synergistic interaction between CDK inhibitors (CDKi) and PARPi. From a translational perspective, multiple clinical trials have confirmed the safety and preliminary efficacy of this combination strategy in solid tumors, particularly demonstrating synergistic antitumor activity in settings of PARPi resistance or in tumors with intact HRR function. The combinatorial approach of CDKi and PARPi, through multi-dimensional mechanistic integration, holds strong potential as a key strategy to overcome PARPi resistance and expand the population of patients who can benefit from this class of therapies.