NSD2 maintains lineage plasticity and castration-resistance in neuroendocrine prostate cancer.

Li, Jia J; Vasciaveo, Alessandro; Karagiannis, Dimitrios; Sun, Zhen; Chen, Xiao; Socciarelli, Fabio; Frankenstein, Ziv; Zou, Min; Pannellini, Tania; Chen, Yu; Gardner, Kevin; Robinson, Brian D; de Bono, Johann; Abate-Shen, Cory; Rubin, Mark A.; Loda, Massimo; Sawyers, Charles L; Califano, Andrea; Lu, Chao and Shen, Michael M (19 July 2023). NSD2 maintains lineage plasticity and castration-resistance in neuroendocrine prostate cancer. (bioRxiv). Cold Spring Harbor Laboratory 10.1101/2023.07.18.549585

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The clinical use of potent androgen receptor (AR) inhibitors has promoted the emergence of novel subtypes of metastatic castration-resistant prostate cancer (mCRPC), including neuroendocrine prostate cancer (CRPC-NE), which is highly aggressive and lethal 1 . These mCRPC subtypes display increased lineage plasticity and often lack AR expression 2-5 . Here we show that neuroendocrine differentiation and castration-resistance in CRPC-NE are maintained by the activity of Nuclear Receptor Binding SET Domain Protein 2 (NSD2) 6 , which catalyzes histone H3 lysine 36 dimethylation (H3K36me2). We find that organoid lines established from genetically-engineered mice 7 recapitulate key features of human CRPC-NE, and can display transdifferentiation to neuroendocrine states in culture. CRPC-NE organoids express elevated levels of NSD2 and H3K36me2 marks, but relatively low levels of H3K27me3, consistent with antagonism of EZH2 activity by H3K36me2. Human CRPC-NE but not primary NEPC tumors expresses high levels of NSD2, consistent with a key role for NSD2 in lineage plasticity, and high NSD2 expression in mCRPC correlates with poor survival outcomes. Notably, CRISPR/Cas9 targeting of NSD2 or expression of a dominant-negative oncohistone H3.3K36M mutant results in loss of neuroendocrine phenotypes and restores responsiveness to the AR inhibitor enzalutamide in mouse and human CRPC-NE organoids and grafts. Our findings indicate that NSD2 inhibition can reverse lineage plasticity and castration-resistance, and provide a potential new therapeutic target for CRPC-NE.

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