CDK7 inhibition suppresses Castration-Resistant Prostate Cancer through MED1 inactivation.
Rasool RU, Natesan R, Deng Q, Aras S, Lal P, Sander Effron S, Mitchell-Velasquez E, Posimo JM, Carskadon S, Baca SC, Pomerantz MM, Siddiqui J, Schwartz LE, Lee DJ, Palanisamy N, Narla G, Den RB, Freedman ML, Brady DC, and Asangani IA. CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation. Cancer Discov 2019.
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.
ePub ahead of print