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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-sphi...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526762/ https://www.ncbi.nlm.nih.gov/pubmed/34656931 http://dx.doi.org/10.1016/j.ebiom.2021.103625 |
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author | Lin, Hui-Ming Mak, Blossom Yeung, Nicole Huynh, Kevin Meikle, Thomas G. Mellett, Natalie A. Kwan, Edmond M. Fettke, Heidi Tran, Ben Davis, Ian D. Mahon, Kate L. Zhang, Alison Stockler, Martin R. Briscoe, Karen Marx, Gavin Crumbaker, Megan Stricker, Phillip D. Du, Pan Yu, Jianjun Jia, Shidong Scheinberg, Tahlia Fitzpatrick, Michael Bonnitcha, Paul Sullivan, David R. Joshua, Anthony M. Azad, Arun A. Butler, Lisa M. Meikle, Peter J. Horvath, Lisa G. |
author_facet | Lin, Hui-Ming Mak, Blossom Yeung, Nicole Huynh, Kevin Meikle, Thomas G. Mellett, Natalie A. Kwan, Edmond M. Fettke, Heidi Tran, Ben Davis, Ian D. Mahon, Kate L. Zhang, Alison Stockler, Martin R. Briscoe, Karen Marx, Gavin Crumbaker, Megan Stricker, Phillip D. Du, Pan Yu, Jianjun Jia, Shidong Scheinberg, Tahlia Fitzpatrick, Michael Bonnitcha, Paul Sullivan, David R. Joshua, Anthony M. Azad, Arun A. Butler, Lisa M. Meikle, Peter J. Horvath, Lisa G. |
author_sort | Lin, Hui-Ming |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8526762 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-85267622021-10-25 Overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase Lin, Hui-Ming Mak, Blossom Yeung, Nicole Huynh, Kevin Meikle, Thomas G. Mellett, Natalie A. Kwan, Edmond M. Fettke, Heidi Tran, Ben Davis, Ian D. Mahon, Kate L. Zhang, Alison Stockler, Martin R. Briscoe, Karen Marx, Gavin Crumbaker, Megan Stricker, Phillip D. Du, Pan Yu, Jianjun Jia, Shidong Scheinberg, Tahlia Fitzpatrick, Michael Bonnitcha, Paul Sullivan, David R. Joshua, Anthony M. Azad, Arun A. Butler, Lisa M. Meikle, Peter J. Horvath, Lisa G. EBioMedicine Research paper 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. Elsevier 2021-10-14 /pmc/articles/PMC8526762/ /pubmed/34656931 http://dx.doi.org/10.1016/j.ebiom.2021.103625 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research paper Lin, Hui-Ming Mak, Blossom Yeung, Nicole Huynh, Kevin Meikle, Thomas G. Mellett, Natalie A. Kwan, Edmond M. Fettke, Heidi Tran, Ben Davis, Ian D. Mahon, Kate L. Zhang, Alison Stockler, Martin R. Briscoe, Karen Marx, Gavin Crumbaker, Megan Stricker, Phillip D. Du, Pan Yu, Jianjun Jia, Shidong Scheinberg, Tahlia Fitzpatrick, Michael Bonnitcha, Paul Sullivan, David R. Joshua, Anthony M. Azad, Arun A. Butler, Lisa M. Meikle, Peter J. Horvath, Lisa G. Overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase |
title | Overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase |
title_full | Overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase |
title_fullStr | Overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase |
title_full_unstemmed | Overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase |
title_short | Overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase |
title_sort | overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase |
topic | Research paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526762/ https://www.ncbi.nlm.nih.gov/pubmed/34656931 http://dx.doi.org/10.1016/j.ebiom.2021.103625 |
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