CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation

Cancer Discov. 2019 Nov;9(11):1538-1555. doi: 10.1158/2159-8290.CD-19-0189. Epub 2019 Aug 29.


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. 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.See related commentary by Russo et al., p. 1490.This article is highlighted in the In This Issue feature, p. 1469.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • AR protein, human
  • MED1 protein, human
  • Mediator Complex Subunit 1
  • Phenylenediamines
  • Pyrimidines
  • Receptors, Androgen
  • THZ1 compound