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FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition.

ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) associated with high-risk human papilloma virus (HPV) infection is a growing clinical problem. The WEE1 kinase inhibitor AZD1775 (WEE1i) overrides cell cycle checkpoints and is being studied in HNSCC regimens. We show that the HPV16 E6/E7 oncoproteins sensitize HNSCC cells to single-agent WEE1i treatment through activation of a FOXM1-CDK1 circuit that drives mitotic gene expression and DNA damage. An isogenic cell system indicated that E6 largely accounts for these phenotypes in ways that extend beyond p53 inactivation. A targeted genomic analysis implicated FOXM1 signaling downstream of E6/E7 expression and analyses of primary tumors and The Cancer Genome Atlas (TCGA) data revealed an activated FOXM1-directed promitotic transcriptional signature in HPV+ versus HPV- HNSCCs. Finally, we demonstrate the causality of FOXM1 in driving WEE1i sensitivity. These data suggest that elevated basal FOXM1 activity predisposes HPV+ HNSCC to WEE1i-induced toxicity and provide mechanistic insights into WEE1i and HPV+ HNSCC therapies.

SUBMITTER: Diab A

PROVIDER: S-EPMC7668037 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition.

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