Abstract 7546: Targeting NSD2 to reverse lineage plasticity and drug resistance in neuroendocrine prostate cancer and subtypes of mCRPC

Abstract Treatment with highly potent anti-androgens, such as enzalutamide and abiraterone promotes lineage plasticity in metastatic castration-resistant prostate cancer (mCRPC), which results in intra-tumor heterogeneity and emergence of mCRPC subtypes. The histological transformation from adenocarcinoma to aggressive neuroendocrine prostate cancer (CRPC-NE) has been associated with a loss of dependency on lineage-survival signals, leading to targeted drug resistance. Epigenomic reprogramming might be a fundamental driver of lineage plasticity. To determine CRPC-NE vulnerabilities, we have performed image-based screening using a small library of antibodies targeting different histone marks on CRPC-NE organoids derived from genetically engineered mice. We find that the histone mark H3K36me2 and the histone methyltransferase NSD2 play important roles in maintain the CRPC-NE epigenetic state. Knockout of NSD2 or ablation of H3K36me2 using an oncohistone mutant H3.3K36M reverted CRPC-NE to an adenocarcinoma phenotype. Simultaneous profiling of the transcriptome and epigenome from single cells verified this lineage conversion and the generation of cell states with canonical AR signaling. Moreover, H3K36me2 or NSD2 depleted mouse and human CRPC-NE organoids responded to enzalutamide treatment in vitro and in vivo, suggesting a reversal of castration-resistance. Most importantly, a small molecule inhibitor of NSD2 in combination with enzalutamide leads to growth suppression or apoptosis of mouse and human CRPC-NE organoids, as well as organoids of other CRPC subtypes. In conclusion, inhibition of NSD2 reverts the epigenomic state of CRPC-NE, reversing lineage plasticity and restoring anti-androgen sensitivity. Thus, we suggest that the combination of NSD2 inhibition with AR inhibition may represent a novel therapeutic approach for patients with CRPC-NE or even other CRPC subtypes. Citation Format: Jia J. Li, Alessandro Vasciaveo, Dimitrios Karagiannis, Xiao Chen, Chen Yu, Andrea Califano, Chao Lu, Michael M. Shen. Targeting NSD2 to reverse lineage plasticity and drug resistance in neuroendocrine prostate cancer and subtypes of mCRPC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7546.