Emerging Strategies to Inhibit the G1/S Transition for Cancer Therapy

Abstract At its core, cancer is a disease of uncontrolled cell proliferation mediated by perturbed molecular pathways that have been elucidated over the past few decades. Biochemical and genetic studies have identified the key molecular regulators of the transition from G1 to S phase in the cell cycle that commits cells to division. During the G1/S transition, the cyclin-dependent kinases CDK4 and CDK6 (CDK4/6) form complexes with cyclin D that phosphorylate and inhibit the retinoblastoma protein (RB). The resulting activation of E2F transcription factors then drives progression into S phase. The centrality of the G1/S transition for proliferation motivated the development of small molecule ATP-competitive CDK4/6 inhibitors, which block the first step of this pathway and are now standard of care for some forms of breast cancer. While successful, these therapeutics have limitations that have motivated the development of alternative approaches to targeting CDKs and the cell cycle. Here, we review how recently developed inhibitors of CDKs and other components of the G1/S pathway may be used, as single agents or in combination therapies, to oppose the growth of human cancers.