Extracellular Matrix in Synthetic Hydrogel-based Prostate Cancer Organoids Regulate Therapeutic Response to EZH2 and DRD2 inhibitors.

Abstract

Following treatment with androgen receptor (AR) pathway inhibitors, ∼20% of prostate cancer patients progress by shedding their AR dependence. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). Currently, no targeted therapies are available for CRPC-NEPCs, and there are minimal organoid models to discover new therapeutic targets against these aggressive tumors. Here, using a combination of patient tumor proteomics, RNA sequencing, spatial omics, immunohistochemistry, and a synthetic hydrogel-based organoid, we define putative extracellular matrix (ECM) cues that regulate the phenotypic, transcriptomic, and epigenetic underpinnings of CRPC-NEPCs. Short-term culture in tumor-expressed ECM differentially regulated DNA methylation and mobilized genes in CRPC-NEPC tumors. The ECM type distinctly regulated the response to small molecule inhibitors of epigenetic repressor EZH2 and Dopamine Receptor D2 (DRD2), the latter being an understudied target in neuroendocrine tumors. In vivo patient-derived xenograft studies in immunocompromised mice showed a robust anti-tumor response when treated with a DRD2 inhibitor. Finally, we demonstrate that therapeutic response in CRPC-NEPCs under drug-resistant ECM conditions can be overcome by first cellular reprogramming with EZH2 inhibitors, followed by DRD2 treatment. The synthetic hydrogel-based organoids suggest the regulatory role ECM may play in therapeutic response to targeted therapies in CRPC-NEPCs and enable the discovery of single drugs and combination therapies\xa0to overcome resistance. This article is protected by copyright. All rights reserved.