Abstract 635P
Background
Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) such as enzalutamide and abiraterone occurs in 20-30% of men with metastatic castration-resistant prostate cancer (mCRPC), and responders will eventually develop resistance. Epidemiological, lipidomic and molecular studies suggest a role of ceramide metabolism in ARSI resistance. Our study aims to investigate the association of the ceramide-S1P (ceramide-S1P) signalling axis with ARSI resistance in mCRPC.
Methods
Lipidomic analysis (>700 lipids) was performed on plasma samples collected from 132 men with mCRPC before starting enzalutamide or abiraterone. AR gene aberrations were identified by deep sequencing of circulating tumour DNA on a subset of the cohort (n=77). Associations between circulating lipids, AR aberrations, radiological progression-free survival (rPFS) and overall survival (OS) were examined. The effect of inhibiting ceramide-S1P signalling with sphingosine kinase (SPHK) inhibitors (PF-543 & ABC294640) on enzalutamide efficacy was investigated with in vitro assays, and transcriptomic and lipidomic analyses of prostate cancer (PC) cell lines (LNCaP, C42B, 22Rv1).
Results
Men with a plasma lipidomic profile of elevated levels of ceramides had shorter rPFS (HR 2.3, 95% CI 1.5-3.6, P = 0.0004), shorter OS (HR 2.3, 95% CI 1.4-3.6, P = 0.0005) and a higher frequency of AR aberrations (58% vs 33%, P = 0.04) than those with the opposite profile. The presence of an AR aberration combined with a lipidomic profile of elevated ceramides was associated with a shorter rPFS and OS, than the presence of only one of these characteristics, or none (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 decreased the IC50 of enzalutamide in PC cell lines by 1.8 to 15 fold (P<0.0008). Transcriptomic and lipidomic analyses indicated that enzalutamide combined with SPHK inhibition enhanced PC cell death by SREBP-induced lipotoxicity.
Conclusions
Overall, these findings indicate that the ceramide-S1P signalling axis may promote ARSI resistance, which can be overcome with SPHK inhibitors.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
NHMRC Australia, CINSW, CCNSW, Movember, PCFA.
Disclosure
E.M. Kwan: Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Other, Honoraria: Janssen; Financial Interests, Personal, Other, Honoraria: Ipsen; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Sponsor/Funding, Travel: Ipsen; Financial Interests, Personal, Other, Honoraria: Astellas Pharma; Financial Interests, Personal, Advisory Role: Astellas Pharma; Financial Interests, Personal, Research Grant: Astellas Pharma; Financial Interests, Personal, Sponsor/Funding, Travel: Astellas Pharma; Financial Interests, Personal, Other, Honoraria: Research Review; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Sponsor/Funding, Travel: Pfizer; Financial Interests, Personal, Sponsor/Funding, Travel: Roche. B. Tran: Financial Interests, Personal, Funding, and personal fees: Amgen; Financial Interests, Personal, Funding, and personal fees: BMS; Financial Interests, Personal, Funding, and personal fees: AstraZeneca; Financial Interests, Personal, Funding, and personal fees: Astellas; Financial Interests, Personal, Funding, and personal fees: Janssen; Financial Interests, Personal, Funding, and personal fees: Pfizer; Financial Interests, Personal, Funding, and personal fees: MSD; Financial Interests, Personal, Funding, and personal fees: Ipsen; Financial Interests, Personal, Funding, and personal fees: Bayer; Financial Interests, Personal, Other, personal fees: IQVIA; Financial Interests, Personal, Other, personal fees: Sanofi; Financial Interests, Personal, Other, personal fees: Tolmar; Financial Interests, Personal, Other, personal fees: Novartis; Financial Interests, Personal, Other, personal fees: Roche. I.D. Davis: Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: ANZUP Cancer Trials Group; Financial Interests, Institutional, Funding: Bayer; Financial Interests, Institutional, Funding: Astellas; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Funding: Merck Shapr & Dome; Non-Financial Interests, Personal, Leadership Role, Chair: ANZUP Cancer Trials Group. A.M. Joshua: Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Astellas. A.A. Azad: Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Speaker’s Bureau: Astellas; Financial Interests, Personal, Speaker’s Bureau: Janssen; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Amgen; Financial Interests, Personal, Speaker’s Bureau: Ipsen; Financial Interests, Personal, Speaker’s Bureau: Bristol Meyers Squibb; Financial Interests, Personal, Speaker’s Bureau: Merck Serono; Financial Interests, Personal, Speaker’s Bureau: Bayer; Financial Interests, Personal, Other, Honoraria: Astellas; Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal, Other, Honoraria: Sanofi; Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Honoraria: Tolmar; Financial Interests, Personal, Other, Honoraria: Telix; Financial Interests, Personal, Other, Honoraria: Merck Serono; Financial Interests, Personal, Other, Honoraria: Janssen; Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: Ipsen; Financial Interests, Personal, Other, Honoraria: Bayer; Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Personal, Other, Honoraria: Amgen; Financial Interests, Personal, Other, Honoraria: Noxopharm; Financial Interests, Personal, Other, Honoraria: Merck Sharpe Dome; Financial Interests, Personal, Advisory Board, scientific: Astellas; Financial Interests, Personal, Advisory Board, scientific: Novartis; Financial Interests, Personal, Advisory Board, scientific: Sanofi; Financial Interests, Personal, Advisory Board, scientific: AstraZeneca; Financial Interests, Personal, Advisory Board, scientific: Tolmar; Financial Interests, Personal, Advisory Board, scientific: Pfizer; Financial Interests, Personal, Advisory Board, scientific: Telix; Financial Interests, Personal, Advisory Board, scientific: Merck Serono; Financial Interests, Personal, Advisory Board, scientific: Janssen; Financial Interests, Personal, Advisory Board, scientific: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, scientific: Ipsen; Financial Interests, Personal, Advisory Board, scientific: Bayer; Financial Interests, Personal, Advisory Board, scientific: Merck Sharpe Dome; Financial Interests, Personal, Advisory Board, scientific: Amgen; Financial Interests, Personal, Advisory Board, scientific: Noxopharm; Financial Interests, Personal, Sponsor/Funding, Travel: Astellas; Financial Interests, Personal, Sponsor/Funding, Travel: Merck Serono; Financial Interests, Personal, Sponsor/Funding, Travel: Amgen; Financial Interests, Personal, Sponsor/Funding, Travel: Novartis; Financial Interests, Personal, Sponsor/Funding, Travel: Janssen; Financial Interests, Personal, Sponsor/Funding, Travel: Tolmar; Financial Interests, Personal, Sponsor/Funding, Travel: Pfizer; Financial Interests, Personal, Research Grant: Astellas; Financial Interests, Personal, Research Grant: Merck Serono; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Aptevo Therapeutics; Financial Interests, Institutional, Research Grant: Glaxo Smith Kline; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: MedImmune; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: SYNthorx; Financial Interests, Institutional, Research Grant: Bionomics; Financial Interests, Institutional, Research Grant: Sanofi Aventis; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Ipsen. L.G. Horvath: Financial Interests, Personal, Research Grant: Astellas; Financial Interests, Personal, Sponsor/Funding, Travel: Janssen; Financial Interests, Personal, Sponsor/Funding, Travel: Pfizer; Financial Interests, Personal, Other, Honoraria: Imagion. All other authors have declared no conflicts of interest.