Abstract
Androgen receptor (AR) signaling inhibitors provide limited survival benefits to patients with prostate cancer (PCa), and worse, few feasible genomic lesions restrict targeted treatment to PCa. Thus, a better understanding of the critical dependencies of PCa may enable more feasible therapeutic approaches to the dilemma. We performed a kinome-scale CRISPR/Cas9 screen and identified cyclin-dependent kinase 12 (CDK12) as being conservatively required for PCa cell survival. Suppression of CDK12 by the covalent inhibitor THZ531 led to an obvious anti-PCa effect. Mechanistically, THZ531 downregulated AR signaling and preferentially repressed a distinct class of CDK12 inhibition-sensitive transcripts (CDK12-ISTs), including prostate lineage-specific genes, and contributed to cellular survival processes. Integration of the super-enhancer (SE) landscape and CDK12-ISTs indicated a group of potential PCa oncogenes, further conferring the sensitivity of PCa cells to CDK12 inhibition. Importantly, THZ531 strikingly synergized with multiple AR antagonists. The synergistic effect may be driven by attenuated H3K27ac signaling on AR targets and an intensive SE-associated apoptosis pathway. In conclusion, we highlight the validity of CDK12 as a druggable target in PCa. The synergy of THZ531 and AR antagonists suggests a potential combination therapy for PCa.
Highlights
The primary therapy for prostate cancer (PCa) is targeting androgen receptor (AR) signaling, while the disease inevitably progresses to castration-resistant prostate cancer (CRPC)
CRISPR/Cas9 screening identifies cyclin-dependent kinase 12 (CDK12) as a conservative kinase target of PCa To identify the highly conservative dependencies of CRPC as the most promising target, we performed a CRISPR screen targeting 507 kinases to detect genes critically required for PCa cells under normal conditions or under enzalutamide-treated culture conditions (Fig. 1A)
To further validate the oncogenic function of SE-driven CDK12ISTs, we focused on GRIN3A, which encodes a subunit of Nmethyl-D-aspartate receptors (NMDARs) [41, 42] and shows a lineage-specific expression pattern in PCa (Fig. 4E)
Summary
The primary therapy for prostate cancer (PCa) is targeting androgen receptor (AR) signaling, while the disease inevitably progresses to castration-resistant prostate cancer (CRPC). Current genome-scale CRISPR/Cas screens have been successfully used to identify genes required for cancer cell survival as candidate targets [9, 10], while their further synergy with existing medicine has been less studied. Studies used CRISPR/Cas screens and focused on specific genes of “synthetic lethality” for clinical drugs, but neglected cancer dependencies under medicated stress [11, 12]. This screening strategy provides potential targets for synergy, while attenuates the applicable value for monotherapy to a certain extent. We first identified cyclin-dependent kinase 12 (CDK12) as conservatively required for PCa cells under both normal and AR antagonism stress conditions, suggesting that CDK12 inhibition may confer synergistic anti-PCa and AR antagonism properties
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
