PT  - JOURNAL ARTICLE
AU  - Daria Bulanova
AU  - Yevhen Akimov
AU  - Wojciech Senkowski
AU  - Jaana Oikkonen
AU  - Laura Gall-Mas
AU  - Sanna Timonen
AU  - Manar Elmadani
AU  - Johanna Hynninen
AU  - Sampsa Hautaniemi
AU  - Tero Aittokallio
AU  - Krister Wennerberg
TI  - A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing drugs in RB1-deficient ovarian and breast cancer cells
AID  - 10.1101/2022.11.14.516369
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.11.14.516369
4099  - http://biorxiv.org/content/early/2022/11/16/2022.11.14.516369.short
4100  - http://biorxiv.org/content/early/2022/11/16/2022.11.14.516369.full
AB  - 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 StatementThe authors have declared no competing interest.