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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-S1P) signalling axis with ARSI resistance in mCRPC. METHODS: Lipidomic analysis ( approximately 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-S1P signalling promotes ARSI resistance, which can be reversed with SPHK inhibitors. FUNDING: None.

Type Journal
ISBN 2352-3964 (Electronic) 2352-3964 (Linking)
Authors Lin, H. M.; Mak, B.; Yeung, N.; Huynh, K.; Meikle, T. G.; Mellett, N. A.; Kwan, E. M.; Fettke, H.; Tran, B.; Davis, I. D.; Mahon, K. L.; Zhang, A.; Stockler, M. R.; Briscoe, K.; Marx, G.; Crumbaker, M.; Stricker, P. D.; Du, P.; Yu, J.; Jia, S.; Scheinberg, T.; Fitzpatrick, M.; Bonnitcha, P.; Sullivan, D. R.; Joshua, A. M.; Azad, A. A.; Butler, L. M.; Meikle, P. J.; Horvath, L. G.
Responsible Garvan Author A/Prof Lisa Horvath
Publisher Name EBioMedicine
Published Date 2021-10-31
Published Volume 72
Published Pages 103625
Status Published in-print
DOI 10.1016/j.ebiom.2021.103625
URL link to publisher's version