FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition

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 WEE1i-induced toxicity and provide mechanistic insights into WEE1i and HPV+ HNSCC therapies.

Co-regulation and function of FOXM1/RHNO1 bidirectional genes in cancer

“…Thus, one model would predict that cells with reduced FOXM1 would have a reduced rate of inherited DNA damage caused by RHNO1 loss ( Cotta-Ramusino et al, 2011 ) due to reduced cell cycle transit of cells with damaged DNA. This model seems to be in agreement with recent reports showing that FOXM1 sensitizes tumor cells to Chk1 and WEE1 inhibitors ( Chung et al, 2019 ; Branigan et al, 2021 ; Diab et al, 2020 ). In contrast, because FOXM1 is also required for proper mitotic progression and disruption of FOXM1 increases mitotic DNA damage ( Laoukili et al, 2005 ), it is plausible that targeting FOXM1 could, in some instances, augment the effects of RHNO1 depletion.…”

Prognostic biomarkers and therapeutic targets in oral squamous cell carcinoma: a study based on cross-database analysis

“…FOXM1 may also act as a therapeutic target against head and neck carcinoma [59,60]. Recent study showed that upregulated basal FOXM1 activity predisposes HPV positive HNSCC to WEE1i-induced toxicity [61]. Consistently, we found that FOXM1 is differentially expressed in OSCC patient with different tumor stages, genders, races, and molecular subtypes.…”

CCNE1 amplification is synthetic-lethal with PKMYT1 kinase inhibition

“…With respect to additional genetic alterations that could benefit from PKMYT1 inhibition, tumors with mutations in FBXW7, which encodes a substrate adaptor for a cullin-RINGligase that targets cyclin E for ubiquitin-dependent proteolysis (11,(47)(48)(49), represents an attractive patient population given that cyclin E drives genome instability in these tumors (50). We finally note that alterations in FOXM1-MMB-driven transcription are seen in multiple cancers (51-53), including HPV-positive head and neck squamous cell carcinoma, where it causes sensitivity to WEE1 inhibition (54). Therefore, testing whether FOXM1-MMB-driven transcription can act as a more general vulnerability to the loss of CDK1 inhibitory phosphorylation may further expand the range of tumors that could benefit from PKMYT1 inhibitors.…”