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 1a (CK1a) as a therapeutic target to overcome ENZA resistance. Depletion or pharmacologic 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, 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 CK1a in the regulation of DNA-damage response.

Document Type

Article

Publication Date

4-2023

Notes/Citation Information

© 2023 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.xcrm.2023.101015

Funding Information

This work was supported by NIH R01 CA157429 (X.L.), R01 CA196634 (X.L.), R01 CA264652 (X.L.), and R01 CA256893 (X.L.). This study was aided by grant #IRG 19-140-31 from the American Cancer Society (J.L.). This research was also supported by the Biospecimen Procurement & Translational Pathology, Biostatistics and Bioinformatics, and Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558). We acknowledge Dr. Joshi Alumkal (University of Michigan, Ann Arbor, MI, USA) for sharing the RNA-seq database from the patients with ENZA treatment. We thank Heather Russell-Simmons at the Markey Cancer Center Research Communications Office and Eleanor Erikson for proof- reading the paper.

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