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
  • 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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