RESUMO
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.
Assuntos
Proteínas de Ciclo Celular/efeitos dos fármacos , Proteína Forkhead Box M1/metabolismo , Infecções por Papillomavirus/tratamento farmacológico , Proteínas Tirosina Quinases/efeitos dos fármacos , Pirazóis/antagonistas & inibidores , Pirimidinonas/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Proteína Quinase CDC2/metabolismo , Pontos de Checagem do Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço , Humanos , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Repressoras/metabolismo , Regulação para CimaRESUMO
The multitude of barriers between the mouth and colon may eliminate swallowed oral bacteria. Ascertaining the presence of the same bacteria in the mouth and colon is methodologically challenging partly because 16S rRNA gene sequencing - the most commonly used method to characterize the human microbiota - has low confidence in taxonomic assignments deeper than genus for most bacteria. As different species of the same genus can have low-level variation across the same 16S rRNA gene region, shotgun sequencing is needed to identify a true overlap. We analyzed a curated, multi-cohort, shotgun metagenomic database with species-level taxonomy and clade-specific marker genes to fill this knowledge gap. Using 500 paired fecal/oral (4 oral sites) samples from 4 healthy adult cohorts, we found a minute overlap between the two niches. Comparing marker genes between paired oral and fecal samples with species-level overlap, the pattern of overlap in only 7 individuals was consistent with same-strain colonization. These findings argue against ectopic colonization of oral bacteria in the distal gut in healthy adults.