NSD2 Expression in Metastatic Castration-Resistant Prostate Cancer
Direct Answer to Your Question
The provided evidence does not specify an exact percentage of mCRPC cells that express NSD2, but research indicates that high NSD2 expression is specifically elevated in human CRPC-NE (neuroendocrine prostate cancer) compared to primary NEPC tumors, and correlates with poor survival outcomes in mCRPC patients. 1
Key Mechanistic Findings About NSD2 in mCRPC
NSD2's Role in Treatment Resistance
NSD2 (Nuclear Receptor Binding SET Domain Protein 2) maintains neuroendocrine differentiation and castration-resistance in CRPC-NE by catalyzing histone H3 lysine 36 dimethylation (H3K36me2). 1
CRPC-NE organoids express elevated levels of NSD2 and H3K36me2 marks, but relatively low levels of H3K27me3, consistent with antagonism of EZH2 activity. 1
Clinical Significance
High NSD2 expression in mCRPC correlates with poor survival outcomes. 1
Human CRPC-NE (but not primary NEPC tumors) expresses high levels of NSD2, consistent with a key role for NSD2 in lineage plasticity. 1
Therapeutic Implications for Clinical Trials
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. 1
NSD2 inhibition can reverse lineage plasticity and castration-resistance, providing a potential new therapeutic target for CRPC-NE. 1
Context for Clinical Trial Design
Current Standard Treatments for mCRPC
For newly diagnosed mCRPC patients, continued ADT with abiraterone acetate plus prednisone, docetaxel, or enzalutamide should be offered. 2
Cabazitaxel is preferred over switching AR inhibitors in patients who have received docetaxel and a novel hormone therapy (CARD trial: HR 0.64 for OS). 3
NSD2 Inhibitor Combination Considerations
- If darolutamide is considered in combination with an NSD2 inhibitor, it would only be appropriate in the context of a clinical trial, as there is no established safety, efficacy, or mechanistic data to support its use in routine clinical practice. 4
Important Caveats
The research demonstrates that NSD2 is particularly relevant in the neuroendocrine subtype of mCRPC (CRPC-NE), which represents a subset of mCRPC cases that emerge after potent AR inhibitor therapy. The exact percentage of all mCRPC cells expressing NSD2 is not quantified in the available evidence, but the expression pattern is clearly enriched in the aggressive neuroendocrine phenotype associated with treatment resistance and lineage plasticity. 1