Dataset Information

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, ?H2AX-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.

SUBMITTER: Diab A

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

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Diab Ahmed A Kao Michael M Kehrli Keffy K Kim Hee Yeon HY Sidorova Julia J Mendez Eduardo E

Molecular cancer research : MCR 20190124 5

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. ...[more]

PMID: 30679201

Similar Datasets

Project description:BACKGROUND: Tumorigenesis is the result of genomic or epigenomic insults and subsequent loss of the proper mechanisms to respond to these alterations leading to unscheduled growth. Tumors arising from these mutations often have altered cell cycles that offer proliferative advantages and lead to the accumulation of additional mutations that can lead to more aggressive phenotypes. Nevertheless, tumor cells must still adhere to the basic tenets of the cell cycle program to ensure their survival by DNA duplication, chromosomal segregation and cytokinesis. The atypical tyrosine kinase Wee1 plays a key role in regulating the cell cycle at the DNA synthesis and mitotic checkpoints via phosphorylation and subsequent inactivation of cyclin-dependent kinases (CDKs) in both healthy and tumorigenic cells. METHODS: To assess the role of Wee1 in tumor cell proliferation we performed small interfering RNA (siRNA) experiments in a panel of diverse cell lines derived from various tissue origins. We also tested the hypothesis that any potential effects would be as a result of the kinase activity of Wee1 by siRNA rescue studies with wild-type or kinase-dead versions of Wee1. RESULTS: We find that, in general, cells with wild-type p53 activity are not susceptible to loss of Wee1 protein via siRNA. However, Wee1 siRNA treatment in tumor cells with an inherent loss of p53 activity results in a deregulated cell cycle that causes simultaneous DNA synthesis and premature mitosis and that these effects are kinase dependent. These cumulative effects lead to potent inhibition of cellular proliferation and ultimately caspase-dependent apoptosis in the absence of co-treatment with cytotoxic agents. CONCLUSIONS: These results suggest that, while Wee1 acts as a tumor suppressor in the context of normal cell growth and its functional loss can be compensated by p53-dependent DNA damage repairing mechanisms, specific inhibition of Wee1 has deleterious effects on the proliferation and survival of p53 inactive tumors. In total, targeting the atypical kinase Wee1 with an siRNA-based therapeutic or a selective ATP competitive small molecule inhibitor would be a feasible approach to targeting p53 inactive tumors in the clinic.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets