CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation
Abstract
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. In vivo, 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 01, 2019
- Source ID
- 10.1158/2159-8290.cd-19-0189
Entities
People
- Daniel J. Lee
- Donita C Brady
- Erick Mitchell-velasquez
- Goutham Narla
- Irfan A. Asangani
- Javed Siddiqui
- Jessica M Posimo
- Lauren E. Schwartz
- Mark M. Pomerantz
- Matthew L Freedman
- Nallasivam Palanisamy
- Priti Lal
- Qu Deng
- Ramakrishnan Natesan
- Reyaz Ur Rasool
- Robert B. Den
- Samuel Sander Effron
- Shannon Carskadon
- Shweta Aras
- Sylvan C. Baca
Organizations
- American Cancer Society
- Harvard Medical School
- Thomas Jefferson University
- United States Department of Defense
- University of Michigan
- University of Pennsylvania
- Vattikuti Urology Institute