Lineage plasticity is a cancer hallmark that drives disease progression and treatment resistance1,2. 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)3,4,5. Here we show that plasticity-associated treatment resistance in CRPC can be reversed through the inhibition of NSD2, a histone methyltransferase6. 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 mice7 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.
谱系可塑性是癌症的标志，驱动疾病进展和治疗耐药[1,2]。可塑性通常由可能可逆的表观遗传机制介导，但此类可逆性的实例很少。在去势抵抗性前列腺癌（CRPC）中，可塑性介导了对雄激素受体（AR）抑制剂的耐药，并促使腺癌向包括神经内分泌前列腺癌（CRPC-NE）在内的侵袭性亚型进展[3,4,5]。本研究发现，CRPC中与可塑性相关的治疗耐药可通过抑制NSD2（一种组蛋白甲基转移酶[6]）而逆转。CRPC-NE中NSD2的上调与较差的患者生存结局相关，且NSD2介导的H3K36二甲基化调节了与神经内分泌分化相关基因的增强子。在利用基因工程小鼠[7]建立的前列腺肿瘤类器官（再现向神经内分泌状态的转分化过程）以及人源CRPC-NE类器官中，CRISPR介导的NSD2靶向作用可使CRPC-NE逆转为腺癌表型。此外，经典的AR信号通路被上调，且对AR抑制剂恩杂鲁胺的应答得以恢复。使用首创小分子药物对NSD2进行药理学抑制可逆转可塑性，并与恩杂鲁胺协同作用，抑制培养物及异种移植模型中多种CRPC亚型的人源患者来源类器官的生长并促进细胞死亡。同时靶向NSD2和AR可能为目前难治的致死性CRPC提供新的治疗策略。
NSD2 targeting reverses plasticity and drug resistance in prostate cancer
肿瘤(癌症)患者之家