Overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase

Abstract

Background: Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) occurs in 20À30% 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¢5À3¢6, p = 0¢0004) and shorter OS (HR=2¢3, 95% CI=1¢4À36, 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

Combined impact of lipidomic and genetic aberrations on clinical outcomes in metastatic castration-resistant prostate cancer

“…There is emerging evidence of a biological link between lipid metabolism and genetic aberrations including AR , RB1 and PI3K on PC growth. Enhanced ceramide-S1P signalling may be mediating ARSI resistance induced by AR gain, as men with mCRPC had significantly shorter ARSI treatment duration if their tumours had AR gain in combination with increased expression of sphingolipid genes (involved in ceramide-S1P signalling) [ 16 ]. Furthermore, de novo resistance to enzalutamide in androgen-independent cells can be reversed with sphingosine kinase inhibitors in vitro [ 16 ].…”

“…Enhanced ceramide-S1P signalling may be mediating ARSI resistance induced by AR gain, as men with mCRPC had significantly shorter ARSI treatment duration if their tumours had AR gain in combination with increased expression of sphingolipid genes (involved in ceramide-S1P signalling) [ 16 ]. Furthermore, de novo resistance to enzalutamide in androgen-independent cells can be reversed with sphingosine kinase inhibitors in vitro [ 16 ]. A recent study demonstrated that a novel fatty acid synthase inhibitor antagonised CRPC growth through metabolic reprogramming and inhibited expression of AR and its variants, including AR-V7 [ 28 ].…”

“…Drugs specifically targeting sphingolipid metabolism are mostly in pre-clinical development in cancer [ 18 ], but a specific inhibitor of sphingosine kinase 2, Opaganib (ABC294640), has been tested in patients with solid tumours [ 44 ]. Recently, we showed that Opaganib can overcome de novo enzalutamide resistance in androgen-independent PC cells in vitro [ 16 ]. Opaganib is currently undergoing a Phase 2 study in combination with AR inhibitors in patients with mCRPC (NCT04207255).…”

Choosing Kinase Inhibitors for Androgen Deprivation Therapy-Resistant Prostate Cancer

“…SK1 is highly expressed in certain types of cancers, including PCa [ 123 ]. SK1 expression level and activity are associated with PCa progression, recurrence, and chemotherapy resistance [ 44 , 123 , 124 ]. AI PCa PC3 cells have much higher SK1 activity than AD PCa LNCaP cells, and SK1 involves in AI survival of PCa cells [ 123 , 125 ].…”

“…FTY720 treatment also sensitizes CRPC cells to radiotherapy. Furthermore, SK1 inhibition overcomes enzalutamide resistance and enhances enzalutamide efficacy in CRPC cells [ 44 , 45 , 46 ]. It was also reported that treatment with SK2 inhibitor ABC294640 reduces CRPC cell growth as well as the expression of c-Myc and AR.…”