A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing drugs in RB1-deficient ovarian and breast cancer cells

Bulanova, Daria; Akimov, Yevhen; Senkowski, Wojciech; Oikkonen, Jaana; Gall-Mas, Laura; Timonen, Sanna; Elmadani, Manar; Hynninen, Johanna; Hautaniemi, Sampsa; Aittokallio, Tero; Wennerberg, Krister

doi:10.1101/2022.11.14.516369

Cited by 3 publications

(3 citation statements)

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“…These included OVCAR3, OVCAR8, COV318, COV362 and KURAMOCHI cell lines. We previously profiled these cell lines for their expression of driver oncogenes ( Supplementary Figure S4C ) ( 42 ). Regardless of the expression of specific driver oncogenes, all ovarian cancer cell lines were eradicated by WEE1i and PKMYT1i following multiple low-dose exposure (Figure 4A – J ).…”

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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“…We previously profiled these cell lines for their expression of driver oncogenes (Suppl.Fig. 3A) (34). Regardless of the expression of specific driver oncogenes, all ovarian cancer cell lines were eradicated by WEE1i and PKMYT1i following multiple low dose exposure (Fig.…”

Section: Wee1i and Pkmyt1i Multiple Low Dose Treatment Is Efficient A...mentioning

confidence: 86%

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

Benada

Bulanova

Azzoni

et al. 2023

Preprint

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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 utilising 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 activation of CDK1. Furthermore, the combined treatment exacerbated DNA replication stress and replication catastrophe, leading to increase of the genomic instability and inflammatory STAT1 signalling activation. Finally, the multiple low dosing was well tolerated in mice. 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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“…Both approaches indicate that RB1 loss is generally clonal, enhancing its value as a therapeutic target if selective inhibitors can be identified. Casein kinase 2 (CK2) inhibitors have been reported to enhance the sensitivity of RB1-deficient TNBC and HGSC cells to carboplatin and niraparib 72 . In addition, Aurora kinase A and B inhibition is synthetically lethal in combination with RB1 loss in breast and lung cancer cells [73][74][75] .…”

Section: Discussionmentioning

confidence: 99%

Concurrent RB1 loss andBRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma

Saner,

Takahashi,

Budden

et al. 2023

Preprint

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BackgroundSomatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes includingBRCA1andBRCA2(BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germlineBRCApathogenic variants and RB1 loss influences long-term survival in a large series of HGSC.Patients and methodsRB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germlineBRCAstatus in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deletedRB1in HGSC cell lines with and withoutBRCA1mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency andRB1loss.ResultsRB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated withRB1mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83,P= 6.8 × 10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03,P= 0.0140). GermlineBRCAmutations and RB1 loss co-occurred in HGSC (P< 0.0001). Patients with both RB1 loss and germlineBRCAmutations had a superior OS (HR 0.38, 95% CI 0.25-0.58,P= 5.2 x10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin (P< 0.01) and paclitaxel (P< 0.05) was seen inBRCA1mutated cell lines withRB1knockout. Among 126 patients with whole-genome and transcriptome sequence data, combinedRB1loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent inBRCA-deficient HGSC with co-loss ofRB1.ConclusionsCo-occurrence of RB1 loss andBRCAmutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

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A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing drugs in RB1-deficient ovarian and breast cancer cells

Cited by 3 publications

References 82 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

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

Concurrent RB1 loss andBRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma

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