A kinome-wide CRISPR screen identifies CK1a as a target to overcome enzalutamide resistance of prostate cancer

Enzalutamide (ENZA), a second-generation androgen receptor antagonist, has significantly increased pro-gression-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 iden-tified casein kinase 1a (CK1a) as a therapeutic target to overcome ENZA resistance. Depletion or pharmaco-logic inhibition of CK1a enhanced ENZA efficacy in ENZA-resistant cells and patient-derived xenografts. Mechanistically, CK1a 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 CK1a stabilizes ATM, re-sulting 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 CK1a in the regulation of DNA-damage response.