FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition.

gnorimies20.15 shared this article with you from Inoreader FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition. Via pubmed: hpv infection FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition. Proc Natl Acad Sci U S A. 2020 Oct 22;: Authors: Diab A, Gem H, Swanger J, Kim HY, Smith K, Zou G, Raju S, Kao M, Fitzgibbon M, Loeb KR, Rodriguez CP, Méndez E, Galloway DA, Sidorova JM, Clurman BE 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 WE E1i-induced toxicity and provide mechanistic insights into WEE1i and HPV+ HNSCC therapies. PMID: 33093209 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.