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

https://doi.org/10.1016/j.xcrm.2023.101015Get rights and content
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Highlights

  • CRISPR screen identifies CK1α as a target to overcome enzalutamide resistance

  • CRISPR screen and RNA-seq illustrate DSB signaling involvement in enzalutamide resistance

  • ATM is a prognostic biomarker to predict the clinical outcome of enzalutamide

  • CK1α-dependent phosphorylation of ATM primes it for proteasomal degradation

Summary

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

prostate cancer
enzalutamide
CRISPR screening
CK1α
ATM

Data and code availability

  • The datasets of CRISPR Screen and RNA-seq are available at NCBI (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE203362), referring to GSE203362.

  • This paper does not generate the original code.

  • Any additional information required to reanalyze the data reported in this work is available from the lead contact upon request.

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