Temporal phosphoproteomics reveals WEE1-dependent control of 53BP1 pathway

Petrosius, Valdemaras; Benada, Jan; Nielsen, Olaf; Schoof, Erwin M.; Sørensen, Claus Storgaard

doi:10.1016/j.isci.2022.105806

Cited by 8 publications

(7 citation statements)

References 76 publications

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“…To evaluate the potential synergistic effect of co-targeting WEE1 and PKMYT1, we conducted a dose response matrix for cell viability with the WEE1 inhibitor adavosertib in combination with the PKMYT1 inhibitor RP-6306 (Figure 1A and B ). The U2OS cell line was selected as a model since it has been well characterized for WEE1 and CDK functions, and notably, investigated in detail for the effects of adavosertib treatment ( 33 ). At 100 nM concentration, the combinatorial treatment led to efficient killing of most U2OS cells (Figure 1B ).…”

Section: Resultsmentioning

confidence: 99%

Synthetic lethal interaction between WEE1 and PKMYT1 is a target for multiple low-dose treatment of high-grade serous ovarian carcinoma

et al. 2023

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Ovarian cancer is driven by genetic alterations that necessitate protective DNA damage and replication stress responses through cell cycle control and genome maintenance. This creates specific vulnerabilities that may be exploited therapeutically. WEE1 kinase is a key cell cycle control kinase, and it has emerged as a promising cancer therapy target. However, adverse effects have limited its clinical progress, especially when tested in combination with chemotherapies. A strong genetic interaction between WEE1 and PKMYT1 led us to hypothesize that a multiple low-dose approach utilizing joint WEE1 and PKMYT1 inhibition would allow exploitation of the synthetic lethality. We found that the combination of WEE1 and PKMYT1 inhibition exhibited synergistic effects in eradicating ovarian cancer cells and organoid models at a low dose. The WEE1 and PKMYT1 inhibition synergistically promoted CDK activation. Furthermore, the combined treatment exacerbated DNA replication stress and replication catastrophe, leading to increase of the genomic instability and inflammatory STAT1 signalling activation. These findings suggest a new multiple low-dose approach to harness the potency of WEE1 inhibition through the synthetic lethal interaction with PKMYT1 that may contribute to the development of new treatments for ovarian cancer.

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Section: Resultsmentioning

confidence: 99%

Synthetic lethal interaction between WEE1 and PKMYT1 is a target for multiple low-dose treatment of high-grade serous ovarian carcinoma

et al. 2023

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“…Similar results were obtained when WEE1 was depleted using siRNA, confirming that WEE1 kinase is the main target of AZD1775 (Figure 2-figure supplement 1H). We then investigated the impact of CDK1 and CDK2, the major kinases controlled by WEE1 31 . The abnormal mitosis phenotype was completely abolished upon combining WEE1 inhibition with RO-3306, a CDK1 inhibitor (Figure 2-figure supplement 1I,J) but not following CDK2 depletion (Figure 2-figure supplement 1K), confirming that the abnormal phenotype was mainly due to the activation of CDK1 after WEE1 inhibition.…”

Section: Resultsmentioning

confidence: 99%

WEE1 kinase inhibition triggers severe chromosome pulverization in aneuploid cells

Haykal,

Rodrigues-Ferreira,

Nahmias

2023

Preprint

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Aneuploidy, a hallmark of cancer, is a prominent feature in breast cancer. Here, we screened a panel of cell cycle kinase inhibitors to identify novel targets for highly aneuploid breast cancers. We show that increasing aneuploidy in breast cancer cells sensitizes to the inhibition of WEE1 kinase. Upon exposure to WEE1 inhibitor, aneuploid cells exhibit aberrant mitosis characterized by the detachment of centromere proteins from centromeric DNA and pulverization of chromosomes. The occurrence of such phenotype is driven by excessive levels of replication stress and DNA damage during S-phase combined with premature entry into mitosis. We show that DNA2 helicase/nuclease is the key player responsible for chromosome pulverization in mitosis. The heightened vulnerability of aneuploid cells to WEE1 inhibition, coupled with underlying molecular mechanisms, provides a rationale for clinical exploration of WEE1-targeted therapies against aneuploid breast cancers.

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“…WEE1 supports genome integrity by suppressing excessive origin firing during DNA replication and premature entry into mitosis [5][6][7]. Consequently, inhibition of WEE1 removes the negative phosphorylation on CDK1/2 (in concert with CDC25) resulting in deregulation of CDKs, increased origin firing and replication fork degradation leading to fork collapse, DNA damage, and unscheduled mitosis [1,[8][9][10]. Recent studies show that WEE1 inhibition by AZD1775 (Adavosertib), a potent and specific small-molecule inhibitor, alone or in combination with DNA damaging agents effectively kills cancer cells of various origins [8,11,12].…”

Section: Introductionmentioning

confidence: 99%

Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia

Malyukova,

Lahnalampi,

Falqués-Costa

et al. 2024

Genome Biol

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Background Targeted therapies exploiting vulnerabilities of cancer cells hold promise for improving patient outcome and reducing side-effects of chemotherapy. However, efficacy of precision therapies is limited in part because of tumor cell heterogeneity. A better mechanistic understanding of how drug effect is linked to cancer cell state diversity is crucial for identifying effective combination therapies that can prevent disease recurrence. Results Here, we characterize the effect of G2/M checkpoint inhibition in acute lymphoblastic leukemia (ALL) and demonstrate that WEE1 targeted therapy impinges on cell fate decision regulatory circuits. We find the highest inhibition of recovery of proliferation in ALL cells with KMT2A-rearrangements. Single-cell RNA-seq and ATAC-seq of RS4;11 cells harboring KMT2A::AFF1, treated with the WEE1 inhibitor AZD1775, reveal diversification of cell states, with a fraction of cells exhibiting strong activation of p53-driven processes linked to apoptosis and senescence, and disruption of a core KMT2A-RUNX1-MYC regulatory network. In this cell state diversification induced by WEE1 inhibition, a subpopulation transitions to a drug tolerant cell state characterized by activation of transcription factors regulating pre-B cell fate, lipid metabolism, and pre-BCR signaling in a reversible manner. Sequential treatment with BCR-signaling inhibitors dasatinib, ibrutinib, or perturbing metabolism by fatostatin or AZD2014 effectively counteracts drug tolerance by inducing cell death and repressing stemness markers. Conclusions Collectively, our findings provide new insights into the tight connectivity of gene regulatory programs associated with cell cycle and cell fate regulation, and a rationale for sequential administration of WEE1 inhibitors with low toxicity inhibitors of pre-BCR signaling or metabolism.

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Temporal phosphoproteomics reveals WEE1-dependent control of 53BP1 pathway

Cited by 8 publications

References 76 publications

Synthetic lethal interaction between WEE1 and PKMYT1 is a target for multiple low-dose treatment of high-grade serous ovarian carcinoma

Synthetic lethal interaction between WEE1 and PKMYT1 is a target for multiple low-dose treatment of high-grade serous ovarian carcinoma

WEE1 kinase inhibition triggers severe chromosome pulverization in aneuploid cells

Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia

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