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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Nature
2026
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/41299174/ |
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Table of Contents:
- NSD2 targeting reverses plasticity and drug resistance in prostate cancer. Li, Jia J Vasciaveo, Alessandro Karagiannis, Dimitris Sun, Zhen Gretarsson, Kristjan H Chen, Xiao Ouerfelli, Ouathek Socciarelli, Fabio Frankenstein, Ziv Dong, Hanyang Zou, Min Yuan, Wei Yang, Guangli Aizenman, Gabriel M Pannellini, Tania Xu, Xinjing Beltran, Himisha Chen, Yu Gardner, Kevin Robinson, Brian D de Bono, Johann Gozani, Or Abate-Shen, Cory Rubin, Mark A Loda, Massimo Sawyers, Charles L Califano, Andrea Lu, Chao Shen, Michael M Male Humans Animals Mice Drug Resistance, Neoplasm Prostatic Neoplasms, Castration-Resistant Benzamides Phenylthiohydantoin Histone-Lysine N-Methyltransferase Receptors, Androgen Nitriles Cell Line, Tumor Organoids Cell Plasticity Repressor Proteins Histones Cell Transdifferentiation Methylation Up-Regulation Adenocarcinoma Gene Expression Regulation, Neoplastic Lineage plasticity is a cancer hallmark that drives disease progression and treatment resistance. Plasticity is often mediated by epigenetic mechanisms that may be reversible; however, there are few examples of such reversibility. In castration-resistant prostate cancer (CRPC), plasticity mediates resistance to androgen receptor (AR) inhibitors and progression from adenocarcinoma to aggressive subtypes, including neuroendocrine prostate cancer (CRPC-NE). Here we show that plasticity-associated treatment resistance in CRPC can be reversed through the inhibition of NSD2, a histone methyltransferase. NSD2 upregulation in CRPC-NE correlates with poor survival outcomes, and NSD2-mediated H3K36 dimethylation regulates enhancers of genes associated with neuroendocrine differentiation. In prostate tumour organoids established from genetically engineered mice that recapitulate the transdifferentiation to neuroendocrine states, and in human CRPC-NE organoids, CRISPR-mediated targeting of NSD2 reverts CRPC-NE to adenocarcinoma phenotypes. Moreover, a canonical AR program is upregulated and responses to the AR inhibitor enzalutamide are restored. Pharmacological inhibition of NSD2 with a first-in-class small molecule reverses plasticity and synergizes with enzalutamide to suppress growth and promote cell death in human patient-derived organoids of multiple CRPC subtypes in culture and in xenografts. Co-targeting of NSD2 and AR may represent a new therapeutic strategy for lethal forms of CRPC that are currently recalcitrant to treatment.