Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition.

ABSTRACT: The p53 gene is the most commonly mutated gene in solid tumors, but leveraging p53 status in therapy remains a challenge. Previously, we determined that p53 deficiency sensitizes head and neck cancer cells to AZD1775, a WEE1 kinase inhibitor, and translated our findings into a phase I clinical trial. Here, we investigate how p53 affects cellular responses to AZD1775 at the molecular level. We found that p53 modulates both replication stress and mitotic deregulation triggered by WEE1 inhibition. Without p53, slowing of replication forks due to replication stress is exacerbated. Abnormal, γH2AX-positive mitoses become more common and can proceed with damaged or underreplicated DNA. p53-deficient cells fail to properly recover from WEE1 inhibition and exhibit fewer 53BP1 nuclear bodies despit

SUBMITTER: Diab A 

PROVIDER: S-EPMC6497558 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature