Overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase

EBioMedicine. 2021 Oct:72:103625. doi: 10.1016/j.ebiom.2021.103625. Epub 2021 Oct 14.


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.

Keywords: Ceramide; Enzalutamide; Metastatic prostate cancer; Sphingosine kinase.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Androstenes / therapeutic use
  • Benzamides / therapeutic use*
  • Biomarkers, Tumor / metabolism
  • Cell Line, Tumor
  • Ceramides / metabolism*
  • Circulating Tumor DNA / metabolism
  • Drug Resistance, Neoplasm / drug effects
  • Humans
  • Lysophospholipids / metabolism*
  • Male
  • Nitriles / therapeutic use*
  • Phenylthiohydantoin / therapeutic use*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Progression-Free Survival
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Receptors, Androgen / metabolism
  • Signal Transduction / drug effects
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism


  • Androstenes
  • Benzamides
  • Biomarkers, Tumor
  • Ceramides
  • Circulating Tumor DNA
  • Lysophospholipids
  • Nitriles
  • Receptors, Androgen
  • Phenylthiohydantoin
  • sphingosine 1-phosphate
  • enzalutamide
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • abiraterone
  • Sphingosine