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 (∼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.
Competing Interests: Declaration of Competing Interest E.M.K.: Honoraria – Janssen, Ipsen, Astellas Pharma, Research Review; Consulting or Advisory Role – Astellas Pharma, Janssen, Ipsen; Research Funding – Astellas Pharma, AstraZeneca; Travel & accommodation – Astellas Pharma, Pfizer, Ipsen, Roche.B.T.: Grants and personal fees – Amgen, AstraZeneca, Astellas, BMS, Janssen, Pfizer, MSD, Ipsen, Bayer; Personal fees – IQVIA, Sanofi, Tolmar, Novartis, Roche.A.Z.: Advisory Role – Astellas; Honoraria – Astellas; Grants and personal fees – Astra Zeneca, Pfizer; Personal fees – Merck Sharp & Dome, Bayer, Mundipharma, Janssen.I.D.D.: Institutional funding – Pfizer, ANZUP Cancer Trials Group, Bayer, Astellas, Janssen, Movember Foundation, Merck Sharp & Dome; Unremunerated chair of ANZUP Cancer Trials Group.T.S.: Travel – Astra Zeneca.D.R.S.: Grants – Regeneron, Amgen, Arrowhead, Espirion, Novartis; Personal fees – Amgen, Sanofi.A.A.: Consultant – Astellas, Janssen, Novartis; Speakers Bureau – Astellas, Janssen, Novartis, Amgen, Ipsen, Bristol Myers Squibb; Merck Serono, Bayer; Honoraria – Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Telix, Merck Serono; Janssen, Bristol Myers Squibb, Ipsen, Bayer, Pfizer, Amgen, Noxopharm, Merck Sharpe Dome; Scientific Advisory Board – Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Pfizer, Telix, Merck Serono; Janssen, Bristol Myers Squibb, Ipsen, Bayer, Merck Sharpe Dome, Amgen, Noxopharm; Travel & accommodation – Astellas, Merck Serono, Amgen, Novartis, Janssen, Tolmar, Pfizer; Investigator research funding – Astellas, Merck Serono, Astra Zeneca; Institutional research funding – Bristol Myers Squibb, Astra Zeneca, Aptevo Therapeutics, Glaxo Smith Kline, Pfizer, MedImmune, Astellas, SYNthorx, Bionomics, Sanofi Aventis, Novartis, Ipsen.A.M.J.: Insitutional funding – Pfizer, Astellas.L.G.H.: Research funding – Astellas; Travel sponsorship – Janssen, Pfizer; Honoraria – Imagion Biosystems. All other authors have declared no conflicts of interest.
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