Abstract 1262: Targeting transcriptional addiction in anti-androgen refractory castration-resistant prostate cancer
Authors: Reyaz ur Rasool, Ramakrishnan Natesan, Qu Deng, Shweta Aras, Samuel Sander Effron, Samuel Sander Effron, Erick Mitchell Velasquez, Jessica M. Posimo, Priti Lal, Donita C. Brady, Irfan A. Asangani
Journal: Cancer Research (2020)

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related mortality in men of the western world. Androgen receptor (AR) is the primary driver alteration in metastatic castration-resistant prostate cancer (mCRPC). Advanced PCa treated with first line androgen-deprivation therapy (ADT) eventually relapse in a hormone refractory or castration-resistant (CR) form. Relapsed disease is highly aggressive and poses an increased risk of morbidity and death. This refractory state of CRPC is characterized by a strong addiction to AR-mediated transcription driven by the synergy between a variety of genomic alterations and epigenetic remodeling. Despite the success of recently approved therapies targeting AR signaling, such as abiraterone and second-generation anti-androgens including enzalutamide, durable responses are limited, owing to acquired resistance. Epigenetic therapies targeting coactivators within the AR transcription machinery have shown promise as effective options for the treatment of CRPC in both its naive and Enzalutamide Resistant state (Enza-Res). Using basic proteomic and next generation genomic approaches, we have identified CDK7, as an indispensable component of the AR-transcription machinery and a novel target in CRPC. The phosphorylation of MED1 (T1457) by CDK7 leads to the formation of the chromatin bound AR-MED1 complex and is essential for its stability and onset of AR-mediated transcription. Loss of CDK7 activity either through genetic silencing or through treatment with the CDK7 inhibitor THZ1 led to de-recruitment of chromatin bound MED1, loss of AR-target gene expressions, increased apoptosis, and a drastic reduction in cell proliferation. Here, we present evidence for the efficacy of targeting CDK7 in curtailing AR signaling in the Enza-Res state. Further, we observed hyper-phosphorylation of MED1 and AR, and a concomitant decrease in the catalytic-subunit (alpha-isoform) of the protein phosphatase 2A (PP2ACα) in enzalutamide resistant cell lines and metastatic biopsies. This hyper-phosphorylated state was strongly dependent on the catalytic activity of CDK7, wherein treatment of Enza-Res cells with THZ1 led to complete loss of phosphorylation of MED1 and AR, and death in Enza-res cells. These findings point to the indispensable role of CDK7 in driving the AR oncogenic transcription program in anti-androgen refractory CRPC and its viability as a potential therapeutic target. Citation Format: Reyaz ur Rasool, Ramakrishnan Natesan, Qu Deng, Shweta Aras, Samuel Sander Effron, Samuel Sander Effron, Erick Mitchell Velasquez, Jessica M. Posimo, Priti Lal, Donita C. Brady, Irfan A. Asangani. Targeting transcriptional addiction in anti-androgen refractory castration-resistant prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1262.