Abstract 3406: GATA2 a novel potential therapeutic target for treatment of neuroendocrine prostate cancer

Neuroendocrine Prostate Cancer (NEPC) is a lethal and aggressive variant of prostate cancer (PC), arises from prostate adenocarcinoma, mainly as a treatment resistant mechanism to Androgen Receptor (AR) signaling inhibitors like enzalutamide. It is independent of AR signaling and characterized by upregulation of neuroendocrine markers like CHGA, SYP, EZH2, MYCN, and CD56. Despite of therapeutic advances, this lethal subtype of PC remains undruggable and has a shorter survival period. Our lab, as well as others, have previously reported several critical functions of GATA2 in AR signaling in PC progression, but the role of GATA2 in NEPC, remained unclear. Here we investigated the role of GATA2 in NEPC using our Patient Derived Xenografts (PDXs), 3D organoid, and 2D cell line models and characterized the pharmacological potency of K-11706, a small molecule inhibitor (SMI) for GATA2 against those NEPC models. To overcome the absence of suitable in vitro models for NEPC, first, we developed 3D organoid and 2D cell line models from NEPC PDX models generated and shared by Dr. Nora Navone at MDACC (mdpc 155-2 and mdpc 144-13). Molecular and histological characterization of these newly developed models showed retention of parent molecular and histological features of their corresponding PDXs. Immunohistochemical characterization of NEPC patient samples and PDXs shows a strong expression of GATA2 protein. Similarly, enzalutamide sensitive cells (16DCRPC cells) showed a significant upregulation of GATA2 mRNA along with neuroendocrine marker genes upon treatment with enzalutamide suggesting upregulation of GATA2 during progression from Castration Resistant Prostate Cancer (CRPC) to NEPC. Pharmacological inhibition of GATA2 by a previously reported SMI, K-11706, efficiently reduced 3D organoid growth and cell viability in vitro, suggesting GATA2 as a potential therapeutic target for NEPC. Gene set enrichment analysis (GSEA) involving our RNA seq data from NEPC cell lines after both K-11706 treatment as well as silencing GATA2 using siRNA (siGATA2) shows a high enrichment score with respect to EZH2 inhibition in curated datasets involving EZH2 inhibition. MTT assay involving a combination of K-11706 and EPZ6438 (EZH2 inhibitor) reduced NEPC cell viability more efficiently than used alone, suggesting a combinational strategy for the treatment of this lethal aggressive PC. NEPC cell line transcriptional profiling and functional pathway analysis of the K-11706 and siGATA2 transcriptomic footprint against curated databases delineated a biological network composed of genes involved in the epithelial mesenchymal transition, hypoxia, genes regulated by NF-kB in response to TNF and KRAS signaling. Based on these results, we propose GATA2 as an actionable therapeutic target for the treatment of NEPC, and pharmacological inhibition of both GATA2 and EZH2 by small molecule inhibitors is effective in NEPC models in vitro. Citation Format: Amit K. Dash, Maria Elisa Ruiz Echartea, Darlene Skapura, Karen Berman de Ruiz, Jenny Jianmin Deng, Cristian Coarfa, Salma Kaochar. GATA2 a novel potential therapeutic target for treatment of neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3406.