Science advances, 2024-05, Vol.10 (21), p.eadj1564-eadj1564
2024
Details
- Autor(en) / Beteiligte
- Titel
- A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing therapeutics in RB1-deficient cancer cells
- Ist Teil von
- Science advances, 2024-05, Vol.10 (21), p.eadj1564-eadj1564
- Ort / Verlag
- United States: American Association for the Advancement of Science
- Erscheinungsjahr
- 2024
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2375-2548eISSN: 2375-2548DOI: 10.1126/sciadv.adj1564Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11114247
- Format
- –
- Schlagworte
- Antineoplastic Agents - pharmacology, Biomedicine and Life Sciences, Cancer, Carboplatin - pharmacology, Casein Kinase II - antagonists & inhibitors, Casein Kinase II - genetics, Casein Kinase II - metabolism, Cell Biology, Cell Line, Tumor, DNA Replication - drug effects, Drug Resistance, Neoplasm - drug effects, Drug Resistance, Neoplasm - genetics, Female, Humans, Ovarian Neoplasms - drug therapy, Ovarian Neoplasms - genetics, Ovarian Neoplasms - metabolism, Ovarian Neoplasms - pathology, Poly(ADP-ribose) Polymerase Inhibitors - pharmacology, Retinoblastoma Binding Proteins - genetics, Retinoblastoma Binding Proteins - metabolism, SciAdv r-articles, Synthetic Lethal Mutations, Triple Negative Breast Neoplasms - drug therapy, Triple Negative Breast Neoplasms - genetics, Triple Negative Breast Neoplasms - metabolism, Triple Negative Breast Neoplasms - pathology, Ubiquitin-Protein Ligases - genetics, Ubiquitin-Protein Ligases - metabolism