Overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase

Background: 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-SIP) signalling axis with ARSI resistance in mCRPC. Methods: Lipidomic analysis (similar to 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). Findings: 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. Interpretation: Ceramide-SIP signalling promotes ARSI resistance, which can be reversed with SPHK inhibitors. (C) 2021 The Authors. Published by Elsevier B.V.

Automated summary

This study focused on investigating the association of ceramide-sphingosine-1-phosphate signalling axis with ARSI resistance in mCRPC. Elevated circulating ceramide levels were found to be associated with shorter radiological progression-free survival and overall survival in men with mCRPC. Combining AR aberrations with elevated ceramide levels resulted in a worse prognosis, and SPHK inhibitors showed potential to enhance the efficacy of enzalutamide.