CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation

• Published in: Cancer discovery 2019-11, Vol.9 (11), p.1538-1555
• Main Authors: Rasool, Reyaz Ur, Natesan, Ramakrishnan, Deng, Qu, Aras, Shweta, Lal, Priti, Sander Effron, Samuel, Mitchell-Velasquez, Erick, Posimo, Jessica M, Carskadon, Shannon, Baca, Sylvan C, Pomerantz, Mark M, Siddiqui, Javed, Schwartz, Lauren E, Lee, Daniel J, Palanisamy, Nallasivam, Narla, Goutham, Den, Robert B, Freedman, Matthew L, Brady, Donita C, Asangani, Irfan A
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cell Proliferation - drug effects; Enhancer Elements, Genetic; Gene Amplification; Gene Expression Regulation, Neoplastic - drug effects; Humans; Male; Mediator Complex Subunit 1 - metabolism; Mice; PC-3 Cells; Phenylenediamines - administration & dosage; Phenylenediamines - pharmacology; Phosphorylation - drug effects; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Pyrimidines - administration & dosage; Pyrimidines - pharmacology; Receptors, Androgen - genetics; Xenograft Model Antitumor Assays
• ISSN: 2159-8274; 2159-8290; 2159-8290
• DOI: 10.1158/2159-8290.CD-19-0189

Metastatic castration-resistant prostate cancer (CRPC) is a fatal disease, primarily resulting from the transcriptional addiction driven by androgen receptor (AR). First-line CRPC treatments typically target AR signaling, but are rapidly bypassed, resulting in only a modest survival benefit with antiandrogens. Therapeutic approaches that more effectively block the AR-transcriptional axis are urgently needed. Here, we investigated the molecular mechanism underlying the association between the transcriptional coactivator MED1 and AR as a vulnerability in AR-driven CRPC. MED1 undergoes CDK7-dependent phosphorylation at T1457 and physically engages AR at superenhancer sites, and is essential for AR-mediated transcription. In addition, a CDK7-specific inhibitor, THZ1, blunts AR-dependent neoplastic growth by blocking AR/MED1 corecruitment genome-wide, as well as reverses the hyperphosphorylated MED1-associated enzalutamide-resistant phenotype. , THZ1 induces tumor regression of AR-amplified human CRPC in a xenograft mouse model. Together, we demonstrate that CDK7 inhibition selectively targets MED1-mediated, AR-dependent oncogenic transcriptional amplification, thus representing a potential new approach for the treatment of CRPC. SIGNIFICANCE: Potent inhibition of AR signaling is critical to treat CRPC. This study uncovers a driver role for CDK7 in regulating AR-mediated transcription through phosphorylation of MED1, thus revealing a therapeutically targetable potential vulnerability in AR-addicted CRPC. . .