Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA.
Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA.
Cell Rep Med. 2023 Apr 18;4(4):101015. doi: 10.1016/j.xcrm.2023.101015.
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.
恩扎鲁胺（ENZA）是第二代雄激素受体拮抗剂，可显著提高转移性前列腺癌（PCa）患者的无进展生存期和总生存期。然而，耐药性仍然是治疗中的一个突出障碍。利用全激酶组 CRISPR-Cas9 敲除筛选，我们鉴定出酪蛋白激酶 1α（CK1α）是克服 ENZA 耐药性的治疗靶点。CK1α 的耗竭或药理学抑制增强了 ENZA 耐药细胞和患者来源异种移植中的 ENZA 疗效。在机制上，CK1α 磷酸化丝氨酸残基 S1270，并调节共济失调毛细血管扩张突变（ATM）的蛋白丰度，ATM 是 DNA 双链断裂（DSB）反应信号的主要启动子，在 ENZA 耐药细胞和患者中受损。CK1α 的抑制稳定了 ATM，从而恢复了 DSB 信号，从而增加了 ENZA 诱导的细胞死亡和生长停滞。我们的研究详细描述了一种治疗 ENZA 耐药性 PCa 的方法，并描述了 CK1α 在调节 DNA 损伤反应中的特定作用。
