FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition
Menée à l'aide de lignées cellulaires de carcinome épidermoïde de la tête et du cou associé au papillomavirus humain, cette étude met en évidence un mécanisme par lequel le facteur de transcription FOXM1 favorise la sensibilité des cellules cancéreuses à l'inhibition de la kinase nucléaire WEE1
HPV+ HNSCC is a growing problem in the United States. We show that HPV16 E6/E7 render HNSCC sensitive to WEE1 inhibition through a CDK1-FOXM1 circuit that drives premature mitosis and requires E6 activities beyond p53 inactivation. Primary HPV+ HNSCCs exhibit high FOXM1 activity, which may underlie their sensitivity to WEE1 inhibition. These data provide a mechanistic rationale for WEE1i incorporation into HPV+ HNSCC treatment.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.All study data are included in the article and supporting information.