FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-11, Vol.117 (45), p.28287-28296
• Main Authors: Diab, Ahmed, Gem, Hakan, Swanger, Jherek, Kim, Hee Yeon, Smith, Kaleb, Zou, Grace, Raju, Sharat, Kao, Michael, Fitzgibbon, Matthew, Loeb, Keith R., Rodriguez, Cristina P., Méndez, Eduardo, Galloway, Denise A., Sidorova, Julia M., Clurman, Bruce E.
• Format: Article
• Language: English
• Subjects: Biological Sciences; Cancer; CDC2 Protein Kinase - metabolism; Cell cycle; Cell Cycle Checkpoints; Cell Cycle Proteins - drug effects; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Circuits; Deactivation; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; Enzyme inhibitors; Forkhead Box Protein M1 - metabolism; Gene expression; Genomes; Genomic analysis; Head & neck cancer; Head and Neck Neoplasms; Health risks; Human papillomavirus; Humans; Inactivation; Kinases; Oncogene Proteins, Viral - metabolism; p53 Protein; Papillomavirus E7 Proteins - metabolism; Papillomavirus Infections - drug therapy; Phenotypes; Protein-Tyrosine Kinases - drug effects; Protein-Tyrosine Kinases - metabolism; Pyrazoles - antagonists & inhibitors; Pyrimidinones - antagonists & inhibitors; Repressor Proteins - metabolism; Sensitivity; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - drug therapy; Toxicity; Transcription; Tumors; Up-Regulation; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2013921117

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) over-rides 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.