Seize the engine: Emerging cell cycle targets in breast cancer

Breast cancer arises from a series of molecular alterations that disrupt cell cycle checkpoints, leading to aberrant cell proliferation and genomic instability. Targeted pharmacological inhibition of cell cycle regulators has long been considered a promising anti-cancer strategy. Initial attempts to drug critical cell cycle drivers were hampered by poor selectivity, modest efficacy and haematological toxicity. Advances in our understanding of the molecular basis of cell cycle disruption and the mechanisms of resistance to CDK4/6 inhibitors have reignited interest in blocking specific components of the cell cycle machinery, such as CDK2, CDK4, CDK7, PLK4, WEE1, PKMYT1, AURKA and TTK. These targets play critical roles in regulating quiescence, DNA replication and chromosome segregation. Extensive preclinical data support their potential to overcome CDK4/6 inhibitor resistance, induce synthetic lethality or sensitise tumours to immune checkpoint inhibitors. This review provides a biological and drug development perspective on emerging cell cycle targets and novel inhibitors, many of which exhibit favourable safety profiles and promising activity in clinical trials. Cell cycle checkpoint disruption drives breast cancer progression. CDK4/6 inhibitors are a mainstay of treatment for hormone receptor-positive breast cancer patients. Cell cycle regulators with promising clinical potential include CDK2, CDK4, CDK7, PLK4, WEE1, PKMYT1, AURKA and TTK. Novel inhibitors of these targets, alone or in combination, may overcome CDK4/6 inhibitor resistance, induce synthetic lethality and sensitise tumours to immunotherapy.image