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

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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.

OriginalsprogEngelsk
Artikelnummereadj1564
TidsskriftScience Advances
Vol/bind10
Udgave nummer21
Antal sider15
ISSN2375-2548
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
Acknowledgments: We thank the staff of the Biomedicum helsinki Flow cytometry Unit, high-content Analysis Unit, high-throughput Biomedicine Unit, and Genomics Unit at the FiMM for providing research infrastructure and excellent technical help. We thank the heRcUleS consortium for providing access to molecularly characterized hGSc patient samples. We thank c. S\u00F8rensen and his team (University of copenhagen) for fruitful discussions that shaped the experimental design and helped data interpretation. Figures 5A and 6 were created with BioRender. Funding: this work was supported by european Union\u2019s 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\u2019s horizon 2020 research and innovation program grant 965193 (decideR) to S.h. and J.h.; european Union\u2019s 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 Jus\u00E9lius Foundation to t.A.; and Academy of Finland (grants 326238, 340141, 345803, and 344698) to t.A. Author contributions: conceptualization: d.B., Y.A., t.A., and K.W. Methodology: d.B., W.S., Y.A., t.A., K.W., and S.h. investigation: d.B., W.S., Y.A., J.O., l.G.-M., M.e., S.t., and J.h. visualization: d.B. Software: Y.A. Formal analysis: d.B., Y.A., J.O., and t.A. data curation: J.O. and J.h. Supervision: t.A., K.W., and S.h. validation: d.B. and S.h. Writing\u2014original draft: d.B. Writing\u2014review and editing: d.B., Y.A., W.S., l.G.-M., S.t., M.e., J.O., J.h., S.h., t.A., and K.W. Resources: W.S., d.B., t.A., K.W., S.h., and J.h. Funding acquisition: W.S., d.B., t.A., K.W., and J.h. Project administration: K.W. Competing interests: the authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

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© 2024 The Authors.

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