PI-039 - TARGETING OF CDK12/13 AND ANDROGEN PATHWAYS IN MESTASTATIC CASTRATION-RESISTANT PROSTATE CANCER

I. Marín-Goñi^1,2, S. Indulkar³, A. John⁴, H. Gao⁵, M. Hernaez^6,7, L. Wang⁸; ¹Mayo Clinic / CIMA University of Navarra, Mayo Clinic - Rochester, MN, USA, ²CIMA University of Navarra, Pamplona, Navarra, Spain, ³Mayo Clinic, Mayo Clinic - Rochester, MN, US, ⁴Mayo Clinic, Mayo Clinic - Rochester, MN, USA, ⁵Yale School of Medicine, Yale School of Medicine, USA, ⁶CIMA University of Navarra, CIMA University of Navarra - Pamplona, Navarra, Spain, ⁷Instituto de Investigacion Sanitaria de Navarra (IDISNA), Pamplona, Navarra, Spain, ⁸Mayo Clinic, Rochester, MN, USA.

Background: : Prostate cancer (PCa) is the most frequently diagnosed male cancer in the U.S. and its advanced stage Castration-Resistant Prostate Cancer (CRPC) has a very poor prognosis. It is well established the central role of the androgen receptor (AR) signalling in both normal prostate tissue and prostate cancer development, progression and therapy resistance. Moreover, molecular subtypes of PCa are driven by different transcription factor signalling activation and transcriptional networks. Our previous studies in bulk RNAseq data from the clinical study PROMOTE in patients with metastatic CRPC (mCRPC) that underwent standard of care therapy (abiraterone acetate/prednisone) have highlighted the significant contributions of dysregulation of transcriptional networks in AR signalling inhibition response and disease progression. Particularly, gene signatures of cell cycle, cell division and DNA damage repair (DDR) processes were associated with response. In this context, CDK12 is an attractive target due to its involvement in regulating transcription and DDR and its recurrent mutation in PCa patients. Previous works have identified CDK12 as a potential target in PCa but less is known of its role in mCRPC and abiraterone resistant settings.

Methods: We evaluated the cytotoxic and synergistic effects with abiraterone (Abi) of a panel of 8 CDK inhibitors in 4 different prostate cancer cell lines and 4 patient-derived xenograft (PDX) organoid models of mCRPC from the PROMOTE study.

Results: Among the 9 drugs and 8 models tested, selective CDK12/13 inhibitors consistently had strong cytotoxic effects at low drug concentrations (IC50s: 30-300nM), regardless of the Abi-resistant status of the PDX-organoids or cell lines. Co-treatment of Abi with SR-4835 (CDK12/13i) showed additive-to-synergistic inhibition of Abi-resistant cell line (Bliss score = 4.9, MSA: 15.35). Additionally, despite the low IC50 of most of the CDK inhibitors in cell lines, only CDK12/13 inhibitors maintained their cytotoxic performance in multiple PDX-organoids.

Conclusion: We demonstrate the effectiveness of CDK12/13 selective inhibitors in mCRPC PDX-derived organoids and their synergistic effects with androgen-targeted therapy, thus highlighting a promising therapeutic strategy that could enhance treatment outcomes for patients with advanced prostate cancer.