RT Journal Article
SR Electronic
T1 A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing drugs in RB1-deficient ovarian and breast cancer cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.14.516369
DO 10.1101/2022.11.14.516369
A1 Daria Bulanova
A1 Yevhen Akimov
A1 Wojciech Senkowski
A1 Jaana Oikkonen
A1 Laura Gall-Mas
A1 Sanna Timonen
A1 Manar Elmadani
A1 Johanna Hynninen
A1 Sampsa Hautaniemi
A1 Tero Aittokallio
A1 Krister Wennerberg
YR 2022
UL http://biorxiv.org/content/early/2022/11/16/2022.11.14.516369.abstract
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.