CDK4/6 inhibitors induce a G1 cell cycle arrest. They have been approved to treat breast cancers and trials are ongoing to test their use in a range of other cancer types. It is important to understand how this G1 arrest corresponds to a cytotoxic response in patients. A prolonged CDK4/6-induced G1 arrest causes a reduction in key replisome components and origin licensing. Upon release from this G1 arrest, DNA replication is impaired and RPE1 cells withdraw from the cell cycle in a p53-dependent manner. In the absence of p53, cells progress through the cell cycle resulting in excessive DNA damage. During this G1 arrest, cells grow excessively which can be rescued by mTOR inhibition, contact inhibition, low serum and MEK inhibition. Rescue of cell growth prevents cell cycle withdrawals and improves long-term proliferation, suggesting that overgrowth is responsible for replication stress defects. This study provides the first link between CDK4/6 inhibitors and genotoxic stress and provides a rationale to predict sensitive tumour types and effective combination strategies.
|Date of Award||2021|
|Sponsors||Medical Research Council|
|Supervisor||Adrian Saurin (Supervisor) & Andrew Hopkins (Supervisor)|
- CDK4/6 inhibitiors
- replication stress
- cell growth