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  • 标题:FOXM1 drives HPV HNSCC sensitivity to WEE1 inhibition
  • 本地全文:下载
  • 作者:Ahmed Diab ; Hakan Gem ; Jherek Swanger
  • 期刊名称:Proceedings of the National Academy of Sciences
  • 印刷版ISSN:0027-8424
  • 电子版ISSN:1091-6490
  • 出版年度:2020
  • 卷号:117
  • 期号:45
  • 页码:28287-28296
  • DOI:10.1073/pnas.2013921117
  • 出版社:The National Academy of Sciences of the United States of America
  • 摘要: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.
  • 关键词:HPV16 ; WEE1 ; AZD1775 ; head and neck cancer ; FOXM1
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