Lineage plasticity is a cancer hallmark that drives disease progressionand treatment resistance1,2. Plasticity is often mediated by epigeneticmechanisms that may be reversible; however, there are few examples of suchreversibility. In castration-resistant prostate cancer (CRPC), plasticity mediatesresistance to androgen receptor (AR) inhibitors and progression from adenocarcinomato aggressive subtypes, including neuroendocrine prostate cancer(CRPC-NE)3–5. Here we show that plasticity-associatedtreatment resistance in CRPC can be reversed through the inhibition of NSD2, ahistone methyltransferase6. NSD2 upregulation in CRPC-NE correlates withpoor survival outcomes, and NSD2-mediated H3K36 dimethylation regulates enhancers ofgenes associated with neuroendocrine differentiation. In prostate tumour organoidsestablished from genetically engineered mice7 that recapitulate thetransdifferentiation to neuroendocrine states, and in human CRPC-NE organoids,CRISPR-mediated targeting of NSD2 reverts CRPC-NEto adenocarcinoma phenotypes. Moreover, a canonical AR program is upregulated andresponses to the AR inhibitor enzalutamide are restored. Pharmacological inhibitionof NSD2 with a first-in-class small molecule reverses plasticity and synergizes withenzalutamide to suppress growth and promote cell death in human patient-derivedorganoids of multiple CRPC subtypes in culture and in xenografts. Co-targeting ofNSD2 and AR may represent a new therapeutic strategy for lethal forms of CRPC thatare currently recalcitrant to treatment.
