A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing therapeutics in RB1-deficient cancer cells
Tekijät: Bulanova, Daria; Akimov, Yevhen; Senkowski, Wojciech; Oikkonen, Jaana; Gall-Mas, Laura; Timonen, Sanna; Elmadani, Manar; Hynninen, Johanna; Hautaniemi, Sampsa; Aittokallio, Tero; Wennerberg, Krister
Kustantaja: American Association for the Advancement of Science
Julkaisuvuosi: 2024
Journal: Science Advances
Tietokannassa oleva lehden nimi: Science advances
Lehden akronyymi: Sci Adv
Artikkelin numero: eadj1564
Vuosikerta: 10
Numero: 21
eISSN: 2375-2548
DOI: https://doi.org/10.1126/sciadv.adj1564
Verkko-osoite: https://www.science.org/doi/10.1126/sciadv.adj1564
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/454721380
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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
Julkaisussa olevat rahoitustiedot:
This work was supported by European Union’s Horizon 2020 research and innovation program grant 667403 (HERCULES) to D.B., Y.A., J.O., S.H., J.H., T.A., and K.W.; European Union’s Horizon 2020 research and innovation program grant 965193 (DECIDER) to S.H. and J.H.; European Union’s Horizon 2020 research and innovation program grant 845045 (RESIST3D) to W.S.; Danish Cancer Society grant R204-A12322 to W.S.; Danish Cancer Society grant R302-A17398 to K.W.; Novo Nordisk Foundation Center for Stem Cell Biology grant NNF17CC0027852 to D.B. and K.W.; Novo Nordisk Foundation Infrastructure grant number NNF20OC0061734 to K.W.; Novo Nordisk Foundation Interdisciplinary Synergy Programme 2021 grant NNF21OC0070381 to K.W. and T.A.; Innovation Fund Denmark/ERA PerMed JTC2020 grant 0204-00005B (PARIS) to K.W.; Cancer Society of Finland to T.A.; Sigrid Jusélius Foundation to T.A.; and Academy of Finland (grants 326238, 340141, 345803, and 344698) to T.A.
