Cyclin-dependent kinase 4; Cyclin-dependent kinase 6 (CDK4; CDK6)

Cyclin-dependent kinase 4 and cyclin-dependent kinase 6 are serine/threonine kinases fundamental for cell cycle control at the G1-S checkpoint. Both enzymes are activated by association with D-type cyclins and drive cell cycle progression by phosphorylating and inactivating the retinoblastoma protein, resulting in E2F release and activation of S-phase genes. Their tight regulation is crucial for normal cell proliferation, and dysregulation leads to uncontrolled growth associated with numerous cancers. CDK4/6 inhibitors are clinically approved and revolutionized the treatment of HR+, HER2-negative breast cancer by inducing cell cycle arrest in malignant cells. Therapeutic challenges include managing hematological adverse events and resistance from genetic alterations in the RB pathway or compensatory CDK activation. While CDK4 and CDK6 are highly homologous and often function redundantly, distinct cellular contexts and regulation mechanisms (e.g., involvement with Hsp90 chaperone in CDK4, nuclear/cytoplasmic localization differences) can influence drug sensitivity and biological roles. These kinases remain among the most validated enzyme targets in cancer therapy, with multiple drugs directly targeting their kinase activity for clinical benefit.

Other names

Cell division protein kinase 4 (CDK4)Cell division protein kinase 6 (CDK6)CDK4/6

Inhibitors block CDK4/6 activity to prevent phosphorylation of RB, maintaining RB tumor suppressor function, stopping E2F-driven S-phase entry and cell proliferation. This leads to cell cycle arrest in G1 phase.