Abstract
Cyclin-dependent kinases 4 and 6 (CDK4/6) are key enzymes that drive the cell cycle from the G1 phase to the S phase, the period of DNA synthesis. In cancer, hyperactivated CDK4/6 promotes uncontrolled proliferation by phosphorylating the retinoblastoma protein (Rb), which leads to the activation of E2F transcription factors. CDK4/6 inhibitors represent a major advancement in targeting dysregulated cell cycle pathways in cancer. Initially approved for hormone receptor-positive breast cancer, these drugs are now under investigation in multiple malignancies. Cancer cells can be CDK4/6-dependent or CDK4/6-independent. Palbociclib is an oral CDK4/6 inhibitor used to treat certain types of breast cancer by slowing cell growth, whereas Trilaciclib is an intravenous CDK4/6 inhibitor used to protect the bone marrow from chemotherapy-induced damage in small cell lung cancer (SCLC). Acute myeloid leukemia (AML) is a heterogeneous disease characterized by diverse genetic abnormalities. Combining CDK4/6 inhibitors with all-trans retinoic acid (ATRA) shows potential for differentiation-based AML treatment, offering a promising avenue for improved outcomes in non-APL AML. Lung cancer is not universally CDK4/6-independent; many subtypes, including some KRAS-mutant lung cancers and p16-null non-small cell lung cancer (NSCLC), are CDK4/6-dependent and show promising results when treated with CDK4/6 inhibitors. Other lung cancers, including SCLC and EGFR-mutant NSCLC with CDK6amplification, are CDK4/6-independent or resistant due to mechanisms such as RB1 loss or alternative cell cycle drivers. Here, we discuss recent translational insights, clinical challenges, and future opportunities for expanding the therapeutic role of CDK4/6 inhibition.