The paper details research into the molecular mechanisms driving resistance to androgen receptor (AR) pathway inhibitors, such as enzalutamide, in advanced Castration-Resistant Prostate Cancer (CRPC). The study specifically addresses the lineage plasticity through which tumors can transdifferentiate into the highly resistant neuroendocrine subtype (CRPC-NE). Investigators identified that the epigenetic regulator NSD2 is significantly upregulated in CRPC-NE, correlating with poor patient survival and driving this shift by increasing H3K36me2 histone marks. Using mouse and human organoid models, the research demonstrated that NSD2 targeting, either through genetic depletion or pharmacological inhibition, effectively reversed the neuroendocrine phenotype. This epigenetic reprogramming restored the tumors' AR expression and, consequently, their sensitivity to enzalutamide both in vitro and in vivo. Ultimately, the findings establish a strong preclinical basis for utilizing combined NSD2 and AR inhibition as a novel strategy to treat advanced and aggressive prostate cancer subtypes.

References:

• Li J J, Vasciaveo A, Karagiannis D, et al. NSD2 targeting reverses plasticity and drug resistance in prostate cancer[J]. Nature, 2025: 1-11.