Send to

Choose Destination
Cancer Discov. 2019 Aug 29. pii: CD-19-0189. doi: 10.1158/2159-8290.CD-19-0189. [Epub ahead of print]

CDK7 inhibition suppresses Castration-Resistant Prostate Cancer through MED1 inactivation.

Author information

Cancer Biology, University of Pennsylvania.
Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania.
Department of Cancer Biology, University of Pennsylvania.
Henry Ford Health System.
Medical Oncology, Dana-Farber Cancer Institute.
Pathology, University of Michigan-Ann Arbor.
Department of Surgery, Hospital of the University of Pennsylvania.
Urology, Henry Ford Health System.
Medicine / Genetics, University of Michigan-Ann Arbor.
Radiation Oncology, Thomas Jefferson University.
Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania.
Cancer Biology, University of Pennsylvania


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 the anti-androgens. 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 co-activator MED1 and AR as a vulnerability in AR-driven CRPC. MED1 undergoes CDK7-dependent phosphorylation at T1457 and physically engages AR at super-enhancer sites, and is essential for AR-mediated transcription. Additionally, a CDK7 specific inhibitor THZ1 blunts AR-dependent neoplastic growth by blocking AR/MED1 co-recruitment genome-wide, as well as reverses the hyper-phosphorylated MED1 associated enzalutamide resistant phenotype. In vivo, THZ1 induces tumor regression of AR amplified castration-resistant human prostate cancer in 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.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center