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 despite evidence of unresolved damage. A faulty G1-S checkpoint propagates this damage into the next division. Together, these deficiencies can intensify damages in each consecutive cell cycle in the drug. IMPLICATIONS: The data encourage the use of AZD1775 in combination with genotoxic modalities against p53-deficient head and neck squamous cell carcinoma.

• Authors: Ahmed Diab, Michael Kao, Keffy Kehrli, Hee Yeon Kim, Julia Sidorova, Eduardo Mendez
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 17 Issue 5 Pg. 1115-1128 (05 2019) ISSN: 1557-3125 [Electronic] United States
• PMID: 30679201 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Pyrazoles
• Pyrimidinones
• TP53 protein, human
• Tumor Suppressor Protein p53
• adavosertib

Topics

• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• DNA Replication (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Head and Neck Neoplasms (drug therapy, genetics)
• Humans
• Mitosis (drug effects)
• Mutation
• Pyrazoles (pharmacology)
• Pyrimidinones (pharmacology)
• Tumor Suppressor Protein p53 (genetics)