CDK4/6 inhibitors prevent cell proliferation by inducing an arrest in G1 of the cell cycle. They are currently approved for clinical use in the treatment of ER+/HER2- breast cancers and in preventing myelosuppression by chemotherapy in the treatment of NSCLC. Given that these inhibitors target fundamental cell cycle enzymes they have potential as pan cancer therapies and are currently being trialled in many different tumour types. Prolonged treatment with these inhibitors can cause cancer cells to become senescent, however the mechanism behind this remains poorly understood. This thesis proposes that during a proliferative arrest, oncogenes in mitogen-dependent signalling pathways drives continued cell growth. This leads to toxic cell hypertrophy which is associated with the cytoplasmic dilution of key replisome components. As a consequence, cells enter S phase with fewer licensed origins of replication and suffer replication stress. The resulting DNA damage, if severe enough, leads to mitotic segregation errors and a loss of proliferative ability. This aberrant increase in cell size is associated with a similar increase in metabolic activity. This has likely impeded the search for biomarkers of sensitivity to these inhibitors as many screens have relied on metabolic proliferation assays which do not accurately characterise the proliferative arrest. A subsequent retrospective analysis of screens using alternative methods reveals potential biomarkers.
Investigating the Mechanisms of Action of CDK4/6 Inhibitors
Foy, R. (Author). 2024
Student thesis: Doctoral Thesis › Doctor of Philosophy