Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia.
Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Chris O' Brien Lifehouse, Camperdown, New South Wales, Australia; University of Sydney, Camperdown, New South Wales, Australia.
EBioMedicine. 2021 Oct;72:103625. doi: 10.1016/j.ebiom.2021.103625. Epub 2021 Oct 14.
Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) occurs in 20-30% of men with metastatic castration-resistant prostate cancer (mCRPC). Ceramide metabolism may have a role in ARSI resistance. Our study's aim is to investigate the association of the ceramide-sphingosine-1-phosphate (ceramide-S1P) signalling axis with ARSI resistance in mCRPC.
Lipidomic analysis (∼700 lipids) was performed on plasma collected from 132 men with mCRPC, before commencing enzalutamide or abiraterone. AR gene aberrations in 77 of these men were identified by deep sequencing of circulating tumour DNA. Associations between circulating lipids, radiological progression-free survival (rPFS) and overall survival (OS) were examined by Cox regression. Inhibition of ceramide-S1P signalling with sphingosine kinase (SPHK) inhibitors (PF-543 and ABC294640) on enzalutamide efficacy was investigated with in vitro assays, and transcriptomic and lipidomic analyses of prostate cancer (PC) cell lines (LNCaP, C42B, 22Rv1).
Men with elevated circulating ceramide levels had shorter rPFS (HR=2·3, 95% CI=1·5-3·6, p = 0·0004) and shorter OS (HR=2·3, 95% CI=1·4-36, p = 0·0005). The combined presence of an AR aberration with elevated ceramide levels conferred a worse prognosis than the presence of only one or none of these characteristics (median rPFS time = 3·9 vs 8·3 vs 17·7 months; median OS time = 8·9 vs 19·8 vs 34·4 months). SPHK inhibitors enhanced enzalutamide efficacy in PC cell lines. Transcriptomic and lipidomic analyses indicated that enzalutamide combined with SPHK inhibition enhanced PC cell death by SREBP-induced lipotoxicity.
Ceramide-S1P signalling promotes ARSI resistance, which can be reversed with SPHK inhibitors.
None.
内在的雄激素受体信号抑制剂（ARSI）抵抗发生在 20-30%的转移性去势抵抗性前列腺癌（mCRPC）男性中。神经酰胺代谢可能在 ARSI 抵抗中发挥作用。我们的研究旨在探讨神经酰胺-鞘氨醇-1-磷酸（ceramide-S1P）信号轴与 mCRPC 中 ARSI 抵抗的关联。
对 132 名 mCRPC 男性在开始使用恩扎鲁胺或阿比特龙之前采集的血浆进行脂质组学分析（约 700 种脂质）。对其中 77 名男性的 AR 基因异常通过循环肿瘤 DNA 的深度测序进行鉴定。通过 Cox 回归分析检测循环脂质与影像学无进展生存期（rPFS）和总生存期（OS）之间的关系。用体外实验研究鞘氨醇激酶（SPHK）抑制剂（PF-543 和 ABC294640）对恩扎鲁胺疗效的抑制作用，并对前列腺癌细胞系（LNCaP、C42B、22Rv1）进行转录组和脂质组学分析。
循环神经酰胺水平升高的男性 rPFS 更短（HR=2.3，95%CI=1.5-3.6，p=0.0004），OS 更短（HR=2.3，95%CI=1.4-36，p=0.0005）。同时存在 AR 异常和神经酰胺水平升高的患者预后比只存在其中一种或都不存在的患者更差（中位 rPFS 时间=3.9 个月、8.3 个月、17.7 个月；中位 OS 时间=8.9 个月、19.8 个月、34.4 个月）。SPHK 抑制剂增强了 PC 细胞系中恩扎鲁胺的疗效。转录组和脂质组学分析表明，恩扎鲁胺联合 SPHK 抑制通过 SREBP 诱导的脂毒性增强 PC 细胞死亡。
神经酰胺-S1P 信号促进 ARSI 抵抗，SPHK 抑制剂可逆转这种抵抗。
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