ABSTRACT: Cyclin-dependent kinases (CDKs) are critical regulators of the cell cycle and play essential roles in DNA repair and maintenance of genome stability. Importantly, dysregulation of CDK activity is a key contributor to oncogenesis. CDKs functionally interact with various regulatory molecules, including cyclins, CDK protein inhibitors, and transcription factors such as p53 and retinoblastoma (RB) proteins. Upon mitogenic stimuli, CDK4/6 binds to cyclin D proteins, leading to hyperphosphorylation of RB proteins, activation of E2F-dependent transcriptional programs, as well as cell cycle initiation and progression. Dysregulation of CDK4/6 action is associated with cancer, and CDK4/6 inhibitors have emerged as very important anticancer therapies. This review will focus on the molecular mechanisms by which CDKs and cyclins regulate the cell cycle, their roles in maintaining genomic integrity, their interactions with RB, and the therapeutic potential of CDK 4/6 inhibitors.

Impact statement: The transition from broad-spectrum kinase inhibitors to selective CDK4/6 inhibitors represents an important
step in oncology, moving away from high-toxicity “pan-CDK” approaches toward targeted, precision medicine.

Key words: CDKs; cyclins; CDK inhibitors; cell cycle; cancer; DDR; RB; E2F transcription factors.