华人学者Nature论文：靶向抑制NSD2，可逆转前列腺癌的可塑性和耐药性

Core Viewpoint - The article discusses the challenges of treating castration-resistant prostate cancer (CRPC), particularly the neuroendocrine subtype (CRPC-NE), and highlights a new dual-targeting therapeutic strategy involving NSD2 and androgen receptor (AR) to address drug resistance and tumor plasticity [1][2][6]. Group 1: CRPC and Its Subtypes - CRPC often retains adenocarcinoma histological features and AR expression but can progress to neuroendocrine subtypes that are highly resistant to AR inhibitors [1][4]. - CRPC-NE occurs in approximately 5%-25% of metastatic CRPC cases and is characterized by aggressive behavior, treatment resistance, and poor clinical prognosis [1][4]. Group 2: NSD2 Targeting Research - A study published in Nature indicates that targeting NSD2 can reverse plasticity and drug resistance in prostate cancer, providing a potential new treatment avenue for lethal CRPC subtypes [2][6]. - NSD2, a histone lysine methyltransferase, plays a crucial role in regulating chromatin structure and gene expression, and its inhibition can successfully reverse treatment resistance in CRPC [4][5]. Group 3: Mechanism of Action - In engineered mouse models and human CRPC-NE organoids, knocking out NSD2 can revert the CRPC-NE phenotype back to adenocarcinoma, restoring sensitivity to AR inhibitors like enzalutamide [5]. - The use of first-in-class NSD2 small molecule inhibitors has shown promise in reversing tumor plasticity and enhancing the efficacy of AR inhibitors in various CRPC subtypes [5][6]. Group 4: Broader Implications - The findings suggest that targeting the NSD2-H3K36me2 signaling axis could serve as an effective treatment strategy for difficult-to-treat cancers, including lung and pancreatic cancers, as indicated by related research [7][9].