WEE1 kinase limits CDK activities to safeguard DNA replication and mitotic entry

Elbæk, Camilla Reiter; Petrosius, Valdemaras; Sørensen, Claus Storgaard

doi:10.1016/j.mrfmmm.2020.111694

Cited by 67 publications

(74 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to orchestrating cell cycle transitions, CDKs regulate cellular checkpoints that sense and respond to genotoxic stresses. CDK1 mediates the G 2 /M checkpoint that prevents mitotic entry in the face of various insults, while CDK2 controls an S phase checkpoint activated by DNA damage and replication stress (3). While numerous mechanisms regulate cyclin-CDKs, reversible CDK inhibitory phosphorylation is particularly important during checkpoint regulation.…”

mentioning

confidence: 99%

FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition

Diab

Gem

Swanger

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

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.

show abstract

mentioning

confidence: 99%

FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition

Diab

Gem

Swanger

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Similarly, expression of a CDK1-T14A variant was well tolerated in parental FT282 fallopian epithelium cells whereas it was toxic in their CCNE1high counterparts. These observations suggest either that PKMYT1 is minimally active in the S phase of normal cells or that the loss of CDK1 inhibitory phosphorylation on Thr14 in cells without CCNE1 amplification is buffered by other modulators of CDK1 activity, such as the CDC25 phosphatases, WEE1 activity, CAK kinase regulation or CDK inhibitors (26). In contrast, in CCNE1-high cells, CDK1 "homeostasis" is impaired causing a vulnerability to the loss of CDK1 inhibitory phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…PKMYT1 encodes an evolutionarily conserved protein kinase, also known as Myt1, whose primary role is the negative regulation of CDK1 both by its inhibitory phosphorylation on Thr14 and its sequestration in the cytoplasm (19)(20)(21)(22)(23). PKMYT1 is structurally related to -and much less studied than -WEE1, which phosphorylates the adjacent Tyr15 residue on CDK1 and CDK2 to inhibit these kinases (24)(25)(26). Unlike WEE1, which is nuclear-localized, PKMYT1 is sequestered in the cytoplasm by an interaction with endomembranes of the Golgi and the endoplasmic reticulum (20,27).…”

mentioning

confidence: 99%

CCNE1 amplification is synthetic-lethal with PKMYT1 kinase inhibition

Gallo

Fourtounis

et al. 2021

Preprint

View full text Add to dashboard Cite

Amplification of the gene encoding cyclin E (CCNE1) is an oncogenic driver in several malignancies and is associated with chemoresistance and poor prognosis. To uncover therapeutic targets for CCNE1-amplified tumors, we undertook genome-scale CRISPR/Cas9-based synthetic lethality screens in cellular models of CCNE1 amplification. Here, we report that increasing CCNE1 dosage engenders a vulnerability to the inhibition of the PKMYT1 kinase, a negative regulator of CDK1. To inhibit PKMYT1, we developed RP-6306, an orally bioavailable and selective inhibitor that shows single-agent activity and durable tumor regressions when combined with gemcitabine in models of CCNE1-amplification. RP-6306 treatment causes unscheduled activation of CDK1 selectively in CCNE1 overexpressing-cells, promoting early mitosis in cells undergoing DNA synthesis. CCNE1 overexpression disrupts CDK1 homeostasis at least in part through an early activation of the FOXM1/MYBL2/MuvB-dependent mitotic transcriptional program. We conclude that PKMYT1 inhibition is a promising therapeutic strategy for CCNE1-amplified cancers.

show abstract

“…Interestingly, we observed that the CDK1 and SKP1 proteins, identified as SYK targets in DG75 and MCF7 cells, respectively, are part of a network of interactions specific to each cell type. CDK1 is the master kinase that controls DNA replication and mitotic entry and is negatively regulated by tyrosine phosphorylation [ 72 , 73 ]. SKP1 is an adaptor component of the SCF E3 ubiquitin ligase complex that exerts an oncogenic function in cancer and that targets regulators of cell cycle progression.…”

Section: Discussionmentioning

confidence: 99%

Comparison of SYK Signaling Networks Reveals the Potential Molecular Determinants of Its Tumor-Promoting and Suppressing Functions

et al. 2021

View full text Add to dashboard Cite

Spleen tyrosine kinase (SYK) can behave as an oncogene or a tumor suppressor, depending on the cell and tissue type. As pharmacological SYK inhibitors are currently evaluated in clinical trials, it is important to gain more information on the molecular mechanisms underpinning these opposite roles. To this aim, we reconstructed and compared its signaling networks using phosphoproteomic data from breast cancer and Burkitt lymphoma cell lines where SYK behaves as a tumor suppressor and promoter. Bioinformatic analyses allowed for unveiling the main differences in signaling pathways, network topology and signal propagation from SYK to its potential effectors. In breast cancer cells, the SYK target-enriched signaling pathways included intercellular adhesion and Hippo signaling components that are often linked to tumor suppression. In Burkitt lymphoma cells, the SYK target-enriched signaling pathways included molecules that could play a role in SYK pro-oncogenic function in B-cell lymphomas. Several protein interactions were profoundly rewired in the breast cancer network compared with the Burkitt lymphoma network. These data demonstrate that proteomic profiling combined with mathematical network modeling allows untangling complex pathway interplays and revealing difficult to discern interactions among the SYK pathways that positively and negatively affect tumor formation and progression.

show abstract

WEE1 kinase limits CDK activities to safeguard DNA replication and mitotic entry

Cited by 67 publications

References 76 publications

FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition

FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition

CCNE1 amplification is synthetic-lethal with PKMYT1 kinase inhibition

Comparison of SYK Signaling Networks Reveals the Potential Molecular Determinants of Its Tumor-Promoting and Suppressing Functions

Contact Info

Product

Resources

About