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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

View ORCID ProfileDaria Bulanova, Yevhen Akimov, Wojciech Senkowski, Jaana Oikkonen, Laura Gall-Mas, Sanna Timonen, Manar Elmadani, Johanna Hynninen, View ORCID ProfileSampsa Hautaniemi, Tero Aittokallio, Krister Wennerberg
doi: https://doi.org/10.1101/2022.11.14.516369
Daria Bulanova
1Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
2Institute for Molecular Medicine Finland, Helsinki Institute for Life Sciences, University of Helsinki, Helsinki, Finland
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  • ORCID record for Daria Bulanova
  • For correspondence: daria.bulanova@helsinki.fi
Yevhen Akimov
2Institute for Molecular Medicine Finland, Helsinki Institute for Life Sciences, University of Helsinki, Helsinki, Finland
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Wojciech Senkowski
1Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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Jaana Oikkonen
3Research Program in Systems Oncology (ONCOSYS), University of Helsinki, Helsinki, Finland
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Laura Gall-Mas
1Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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Sanna Timonen
2Institute for Molecular Medicine Finland, Helsinki Institute for Life Sciences, University of Helsinki, Helsinki, Finland
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Manar Elmadani
4Finnish Red Cross Blood Service, Helsinki, Finland
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Johanna Hynninen
5Department of Obstetrics and Gynecology, Turku University Hospital and University of Turku, Turku, Finland
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Sampsa Hautaniemi
3Research Program in Systems Oncology (ONCOSYS), University of Helsinki, Helsinki, Finland
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Tero Aittokallio
2Institute for Molecular Medicine Finland, Helsinki Institute for Life Sciences, University of Helsinki, Helsinki, Finland
6Institute for Cancer Research, Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway
7Oslo Centre for Biostatistics and Epidemiology (OCBE), University of Oslo, Oslo, Norway
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Krister Wennerberg
1Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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Abstract

Treatment of patients with high-grade serous ovarian carcinoma (HGSOC) and triple-negative breast cancer (TNBC) includes platinum-based drugs, gemcitabine, and PARP inhibitors. However, resistance to these therapies develops in most cases, highlighting the need for novel therapeutic approaches and biomarkers to guide the optimal treatment choice. Using a CRISPR loss-of-function screen for carboplatin sensitizers in the HGSOC cell line OVCAR8, we identified CSNK2A2, the gene encoding for the alpha’ (α’) catalytic subunit of casein kinase 2 (CK2). Expanding on this finding, we confirmed that the CK2 inhibitors silmitasertib and SGC-CK2-1 sensitized many, but not all, TNBC and HGSOC cell lines to the drugs that perturb DNA replication, including platinum drugs, gemcitabine, and PARP inhibitors. We identified RB1 tumor suppressor deficiency as a prerequisite context for the CK2 inhibition-mediated sensitization to these therapeutics. In RB1-deficient cells, CK2 inhibition resulted in accumulation of cells in S phase of the cell cycle, associated with micronuclei formation, and accelerated PARP inhibitor-induced aneuploidy and mitotic cell death. Patient HGSOC organoids that lacked RB1 expression displayed an enhanced long-term response to carboplatin and PARP inhibitor niraparib when combined with silmitasertib, suggesting RB1-stratified efficacy in patients. As RB1 deficiency affects up to 25% of HGSOC and 40% of TNBC cases, CK2 inhibition, proven safe from previous clinical exploration with silmitasertib, is a promising approach to overcome resistance to standard therapeutics in large strata of patients.

Competing Interest Statement

The authors have declared no competing interest.

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Posted November 16, 2022.
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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
Daria Bulanova, Yevhen Akimov, Wojciech Senkowski, Jaana Oikkonen, Laura Gall-Mas, Sanna Timonen, Manar Elmadani, Johanna Hynninen, Sampsa Hautaniemi, Tero Aittokallio, Krister Wennerberg
bioRxiv 2022.11.14.516369; doi: https://doi.org/10.1101/2022.11.14.516369
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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
Daria Bulanova, Yevhen Akimov, Wojciech Senkowski, Jaana Oikkonen, Laura Gall-Mas, Sanna Timonen, Manar Elmadani, Johanna Hynninen, Sampsa Hautaniemi, Tero Aittokallio, Krister Wennerberg
bioRxiv 2022.11.14.516369; doi: https://doi.org/10.1101/2022.11.14.516369

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