Overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase
Hui-Ming Lin,
Blossom Mak,
Nicole Yeung,
Kevin Huynh,
Thomas G. Meikle,
Natalie A. Mellett,
Edmond M. Kwan,
Heidi Fettke,
Ben Tran,
Ian D. Davis,
Kate L. Mahon,
Alison Zhang,
Martin R. Stockler,
Karen Briscoe,
Gavin Marx,
Megan Crumbaker,
Phillip D. Stricker,
Pan Du,
Jianjun Yu,
Shidong Jia,
Tahlia Scheinberg,
Michael Fitzpatrick,
Paul Bonnitcha,
David R. Sullivan,
Anthony M. Joshua,
Arun A. Azad,
Lisa M. Butler,
Peter J. Meikle,
Lisa G. Horvath
Affiliations
Hui-Ming Lin
Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia
Blossom Mak
Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Chris O’ Brien Lifehouse, Camperdown, New South Wales, Australia; University of Sydney, Camperdown, New South Wales, Australia
Nicole Yeung
Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia
Kevin Huynh
Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
Thomas G. Meikle
Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
Natalie A. Mellett
Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
Edmond M. Kwan
Department of Medical Oncology, Monash Health, Clayton, Victoria, Australia; Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia
Heidi Fettke
Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
Ben Tran
Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
Ian D. Davis
Cancer Services, Eastern Health, Box Hill, Victoria, Australia; Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia
Kate L. Mahon
Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia; Chris O’ Brien Lifehouse, Camperdown, New South Wales, Australia; University of Sydney, Camperdown, New South Wales, Australia; Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
Alison Zhang
Chris O’ Brien Lifehouse, Camperdown, New South Wales, Australia
Martin R. Stockler
Chris O’ Brien Lifehouse, Camperdown, New South Wales, Australia; University of Sydney, Camperdown, New South Wales, Australia; Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; Concord Repatriation General Hospital, Concord, New South Wales, Australia
Karen Briscoe
Mid North Coast Cancer Institute, Coffs Harbour, New South Wales, Australia
Gavin Marx
Sydney Adventist Hospital, Wahroonga, New South Wales, Australia
Megan Crumbaker
Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia; The Kinghorn Cancer Centre, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
Phillip D. Stricker
Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia
Pan Du
Predicine, Inc., Hayward, CA, USA
Jianjun Yu
Predicine, Inc., Hayward, CA, USA
Shidong Jia
Predicine, Inc., Hayward, CA, USA
Tahlia Scheinberg
Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Chris O’ Brien Lifehouse, Camperdown, New South Wales, Australia; University of Sydney, Camperdown, New South Wales, Australia
Michael Fitzpatrick
NSW Health Pathology, Camperdown, New South Wales, Australia
Paul Bonnitcha
University of Sydney, Camperdown, New South Wales, Australia; NSW Health Pathology, Camperdown, New South Wales, Australia
David R. Sullivan
Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; NSW Health Pathology, Camperdown, New South Wales, Australia
Anthony M. Joshua
Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia; The Kinghorn Cancer Centre, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
Arun A. Azad
Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
Lisa M. Butler
Adelaide Medical School and Freemason's Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
Peter J. Meikle
Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
Lisa G. Horvath
Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia; Chris O’ Brien Lifehouse, Camperdown, New South Wales, Australia; University of Sydney, Camperdown, New South Wales, Australia; Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; Corresponding author at: Chris O’ Brien Lifehouse, 119-143 Missenden Rd, Camperdown, New South Wales 2050, Australia.
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.
