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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

1
Cancer Biology, University of Pennsylvania.
2
Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania.
3
Department of Cancer Biology, University of Pennsylvania.
4
Henry Ford Health System.
5
Medical Oncology, Dana-Farber Cancer Institute.
6
Pathology, University of Michigan-Ann Arbor.
7
Department of Surgery, Hospital of the University of Pennsylvania.
8
Urology, Henry Ford Health System.
9
Medicine / Genetics, University of Michigan-Ann Arbor.
10
Radiation Oncology, Thomas Jefferson University.
11
Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania.
12
Cancer Biology, University of Pennsylvania asangani@upenn.edu.

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 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.

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