open access publication

Article, 2024

A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing therapeutics in RB1-deficient cancer cells

Science Advances, ISSN 2375-2548, Volume 10, 21, Page eadj1564, 10.1126/sciadv.adj1564

Contributors

Bulanova, Daria R [1] [2] Akimov, Yevhen A 0000-0003-0413-2564 [1] Senkowski, Wojciech 0000-0001-8120-1944 [2] Oikkonen, Jaana 0000-0002-1063-2736 [3] Gall-Mas, Laura 0000-0002-0420-2334 [2] Timonen, Sanna H 0000-0002-8139-5950 [1] Elmadani, Manar F 0009-0001-8832-0812 [4] Hynninen, Johanna 0000-0002-0854-7225 [5] Hautaniemi, Sampsa Kalervo 0000-0002-7749-2694 [3] Aittokallio, Tero A 0000-0002-0886-9769 [1] [6] [7] Wennerberg, Krister 0000-0002-1352-4220 (Corresponding author) [2]

Affiliations

  1. [1] Institute for Molecular Medicine Finland
    2. [NORA names: Finland; Europe, EU; Nordic; OECD];
  2. [2] University of Copenhagen
    3. [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD];
  3. [3] University of Helsinki
    4. [NORA names: Finland; Europe, EU; Nordic; OECD];
  4. [4] Finnish Red Cross
    5. [NORA names: Finland; Europe, EU; Nordic; OECD];
  5. [5] University of Turku
    6. [NORA names: Finland; Europe, EU; Nordic; OECD];

Abstract

Resistance to therapy commonly develops in patients with high-grade serous ovarian carcinoma (HGSC) and triple-negative breast cancer (TNBC), urging the search for improved therapeutic combinations and their predictive biomarkers. Starting from a CRISPR knockout screen, we identified that loss of RB1 in TNBC or HGSC cells generates a synthetic lethal dependency on casein kinase 2 (CK2) for surviving the treatment with replication-perturbing therapeutics such as carboplatin, gemcitabine, or PARP inhibitors. CK2 inhibition in RB1-deficient cells resulted in the degradation of another RB family cell cycle regulator, p130, which led to S phase accumulation, micronuclei formation, and accelerated PARP inhibition-induced aneuploidy and mitotic cell death. CK2 inhibition was also effective in primary patient-derived cells. It selectively prevented the regrowth of RB1-deficient patient HGSC organoids after treatment with carboplatin or niraparib. As about 25% of HGSCs and 40% of TNBCs have lost RB1 expression, CK2 inhibition is a promising approach to overcome resistance to standard therapeutics in large strata of patients.

Keywords

CRISPR, CRISPR knockout screen, PARP, PARP inhibitors, RB1, RB1 expression, Rb1-deficient cells, S-phase accumulation, accumulation, aneuploidy, biomarkers, breast cancer, cancer, cancer cells, carboplatin, carcinoma, casein, casein kinase 2, casein kinase 2 inhibition, cell cycle regulation, cell death, cells, combination, cycle regulation, death, degradation, dependence, expression, formation, gemcitabine, high-grade serous ovarian carcinoma, high-grade serous ovarian carcinoma cells, inhibition, inhibitors, kinase 2, knockout screen, loss, loss of RB1, micronuclei, micronuclei formation, mitotic cell death, niraparib, organoids, ovarian carcinoma, p130, patient-derived cells, patients, predictive biomarkers, primary patient-derived cells, regrowth, regulation, resistance, resistance to therapy, response, screening, search, serous ovarian carcinoma, standard therapeutics, strata, strata of patients, synthetic lethal dependence, therapeutic combinations, therapeutics, therapy, treatment, triple-negative breast cancer

Funders

  • Danish Cancer Society
  • Cancer Society of Finland
  • Academy of Finland
  • Innovation Fund Denmark
  • Novo Nordisk Foundation
  • European Commission
  • VTT Technical Research Centre of Finland
  • Sigrid Jusélius Foundation

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