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Dr. Asangani and his team at the University of Pennsylvania have developed a new approach for the treatment of CRPC by blocking AR signaling at the transcriptional level. The researchers found that AR transcriptional activity relies on activation through a “phosphoswitch” catalyzed by CDK7.
CDK7 phosphorylates the co-activator MED1 which forms a complex with AR leading to AR-mediated gene transcription. Inhibition of CDK7 disrupts the formation of this MED1-AR complex and blocks AR function. This approach allows to overcome several resistance mechanisms including AR amplification, mutation, and de novo androgen synthesis.