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- W4366266983 abstract "Enzalutamide (ENZA), a second-generation androgen receptor antagonist, has significantly increased progression-free and overall survival of patients with metastatic prostate cancer (PCa). However, resistance remains a prominent obstacle in treatment. Utilizing a kinome-wide CRISPR-Cas9 knockout screen, we identified casein kinase 1α (CK1α) as a therapeutic target to overcome ENZA resistance. Depletion or pharmacologic inhibition of CK1α enhanced ENZA efficacy in ENZA-resistant cells and patient-derived xenografts. Mechanistically, CK1α phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DSB signaling, and thus increases ENZA-induced cell death and growth arrest. Our study details a therapeutic approach for ENZA-resistant PCa and characterizes a particular perspective for the function of CK1α in the regulation of DNA-damage response." @default.
- W4366266983 created "2023-04-20" @default.
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- W4366266983 date "2023-04-01" @default.
- W4366266983 modified "2023-10-13" @default.
- W4366266983 title "A kinome-wide CRISPR screen identifies CK1α as a target to overcome enzalutamide resistance of prostate cancer" @default.
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- W4366266983 doi "https://doi.org/10.1016/j.xcrm.2023.101015" @default.
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