2. Academic Validation
  3. A kinome-wide CRISPR screen identifies CK1α as a target to overcome enzalutamide resistance of prostate cancer

A kinome-wide CRISPR screen identifies CK1α as a target to overcome enzalutamide resistance of prostate cancer

  • Cell Rep Med. 2023 Apr 18;4(4):101015. doi: 10.1016/j.xcrm.2023.101015.
Jinghui Liu 1,  Yue Zhao 2,  Daheng He 3,  Katelyn M Jones 1,  Shan Tang 2,  Derek B Allison 4,  Yanquan Zhang 1,  Jing Chen 5,  Qiongsi Zhang 1,  Xinyi Wang 1,  Chaohao Li 1,  Chi Wang 3,  Lang Li 2,  Xiaoqi Liu 6
Affiliations

Affiliations

  • 1 Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA.
  • 2 Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA.
  • 3 Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
  • 4 Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40536, USA.
  • 5 Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
  • 6 Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA. Electronic address: [email protected].
PMID: 37075701 DOI: 10.1016/j.xcrm.2023.101015
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.

Keywords

ATM; CK1α; CRISPR screening; enzalutamide; prostate cancer.

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