Prostate cancer is the most prevalent cancer in men, comprising 20% of all new cancer cases in United States, as per the Cancer Statistics, 2019. Many therapies for prostate cancer function by lowering androgen levels and include androgen deprivation therapy alone or in combination with surgical or chemical castration. Hormone therapy has been a mainstay treatment for prostate cancer, ultimately leading to progression free disease in over 80% of patients over short time periods. Unfortunately, these effects are not durable, and the majority of patients experience progressive disease. Ultimately, the disease progresses and becomes invasive and lethal in the form of castration-resistant prostate cancer (CRPC). Understanding the mechanism by which prostate cancer cells lose their inherent dependence on the canonical androgen signaling pathway for survival has been critical in developing new therapeutic options for patients with CRPC. CDK9 may constitute one such mechanism. CDK9 phosphorylates RNA polymerase II (RNA Pol II), resulting in gene transcription of anti-apoptotic proteins such as MCL1, that can influence prostate cancer cell survival. Additionally, CDK9 is known to phosphorylate the androgen receptor (AR) and both AR and RNA Pol II cooperate for transcription of key prostate cancer genes, including PSA. Therefore, inhibition of CDK9 has great potential to halt constitutive activity of both AR and the RNA Pol II -driven transcriptional program that drives CRPC. Here, we describe tumor growth inhibition in CRPC models using the CDK9 inhibitor TP-1287, an oral alvocidib prodrug, alone and in combination with docetaxel or venetoclax, a BCL-2 inhibitor that is currently being evaluated in a Phase II clinical trial for metastatic CRPC. The CDK9 inhibitor alvocidib demonstrates low nanomolar IC50 values in CRPC cell lines PC3, 22Rv1 and castration dependent PCa cell lines VCAP and LnCAP ranging from 25-175 nM. Alvocidib treatment inhibits RNA Pol II in 22Rv1 cells (~50%) at 80 and 160 nM, 3 and 24 hrs post treatment and regulates MCL-1 protein expression in PC3 cells (300 nM, 24 hrs). Alvocidib treatment also inhibited AR phosphorylation at Ser 81, reducing PSA gene expression (~50%) and inducing caspase activation in 22Rv1 cells (80-160 nM for 24 hrs). We explored the tumor growth inhibition of TP-1287, in several PCa xenograft models namely PC3, 22Rv1, LnCAP and C4-2 models. In androgen sensitive models, 1.25 mpk BID TP-1287 combined well with 10 mpk docetaxel, demonstrating 90% and 81% TGI in C4-2 and LnCAP models respectively. TP-1287 treatment (1.25 mpk BID) in combination with 100 mpk venetoclax demonstrated 64% tumor growth inhibition in the 22Rv1 CRPC model that was resistant to docetaxel, enzalutamide and venetoclax alone. These data support the potential of TP-1287 to be used in combination with currently available or novel therapies to achieve better efficacy for androgen sensitive and CRPC patients.

Citation Format: Tetyana V Forostyan, Evita Weagel, Yuta Matsumura, Ethika Tyagi, Jason M Foulks, Clifford J Whatcott, Adam Siddiqui-Jain, David J Bearss, Steven L Warner. Targeting CDK9 and MCL1 in castration-sensitive and resistant prostate cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C081. doi:10.1158/1535-7163.TARG-19-C081