Background: Treatment with androgen receptor (AR) signaling inhibitors, such as enzalutamide, can induce neural lineage plasticity in prostate cancer, potentially progressing to t-NEPC. However, the molecular mechanisms underlying this enzalutamide-driven plasticity, particularly the contribution of immune signaling pathways, remain poorly understood. Methods: We analyzed transcriptomic profiles of patient samples and prostate cancer cell lines to investigate changes in immune signaling pathways. Interferon gamma (IFNγ), interferon alpha (IFNα), and interleukin 6 (IL6)-Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling were assessed in enzalutamide-sensitive and -resistant prostate cancer cells. Functional assays were conducted to examine cell responsiveness to cytokine stimulation and susceptibility to STAT1 inhibition using fludarabine. Results: Immune-related pathways, including IFNγ, IFNα, IL6-JAK-STAT3, and inflammatory responses, were significantly suppressed in NEPC patient samples compared to those with castration-resistant prostate cancer (CRPC). Enzalutamide-resistant and NEPC cells exhibited markedly impaired IFNγ and IL6 signaling. In contrast, early-stage enzalutamide treatment paradoxically enhanced IFNγ and IL6 responsiveness. Transcriptomic profiling revealed coordinated upregulation of E2F target genes and activation of IFNα/IFNγ and JAK/STAT signaling pathways during early treatment. Importantly, these early-stage cells remained highly sensitive to IFNγ and IL6 stimulation and showed increased susceptibility to STAT1 inhibition by fludarabine, a sensitivity that was lost in resistant cells. Conclusions: Early enzalutamide treatment enhances immune responsiveness, while the development of resistance is associated with suppressed immune signaling and increased lineage plasticity. These results suggest a therapeutic window where combining enzalutamide with STAT inhibitors may delay or prevent lineage plasticity and resistance.
背景：雄激素受体（AR）信号通路抑制剂（如恩杂鲁胺）治疗可诱导前列腺癌发生神经谱系可塑性，可能进展为治疗相关的神经内分泌前列腺癌（t-NEPC）。然而，这种由恩杂鲁胺驱动的可塑性背后的分子机制，特别是免疫信号通路的参与，目前尚不清楚。方法：我们分析了患者样本和前列腺癌细胞系的转录组谱，以研究免疫信号通路的变化。在恩杂鲁胺敏感和耐药的前列腺癌细胞中评估了干扰素γ（IFNγ）、干扰素α（IFNα）以及白细胞介素6（IL6）-Janus激酶（JAK）-信号转导与转录激活因子3（STAT3）信号通路。通过功能实验检测细胞对细胞因子刺激的反应性，以及使用氟达拉滨抑制STAT1后的敏感性。结果：与去势抵抗性前列腺癌（CRPC）患者样本相比，NEPC患者样本中的免疫相关通路，包括IFNγ、IFNα、IL6-JAK-STAT3和炎症反应通路，均显著受到抑制。恩杂鲁胺耐药细胞和NEPC细胞表现出明显受损的IFNγ和IL6信号传导。相比之下，早期阶段的恩杂鲁胺治疗却反常地增强了细胞对IFNγ和IL6的反应性。转录组分析显示，在治疗早期，E2F靶基因协同上调，同时IFNα/IFNγ和JAK/STAT信号通路被激活。重要的是，这些早期阶段的细胞对IFNγ和IL6刺激仍保持高度敏感，并且对氟达拉滨抑制STAT1的敏感性增加，而这种敏感性在耐药细胞中丧失。结论：早期恩杂鲁胺治疗增强了免疫反应性，而耐药性的产生则与免疫信号抑制和谱系可塑性增加相关。这些结果表明存在一个治疗窗口期，在此期间将恩杂鲁胺与STAT抑制剂联合使用，可能延缓或阻止谱系可塑性和耐药性的发生。
肿瘤(癌症)患者之家