Exosomal transfer of acid sphingomyelinase contributes to drug resistance in multiple myeloma

Research output: Unpublished contribution to conferencePoster

Abstract

Multiple myeloma (MM) is well-known for the development of drug resistance, leading to the need for multiple treatment lines at times of relapse or progression. In this study, we identified changes in lipid content in MM patients and further investigated this altered metabolism in vitro.
Lipidomics analysis of plasma samples revealed an increase in ceramides and a decrease in sphingomyelin in MM patients. Therefore, we believe that the enzyme sphingomyelinase, which converts sphingomyelin into ceramide, is upregulated in MM, which we confirmed on primary CD138+ MM cells for acid sphingomyelinase (ASM). We also observed an increase in ASM on both RNA and protein level after melphalan and bortezomib treatment (two standard-of-care drugs) in MM cell lines (OPM2, JJN3, LP1 and U266). Furthermore, these drugs stimulated exosome secretion and induced higher levels of ASM in these exosomes. U266-derived exosomes, containing high amounts of ASM, increased cell viability compared to ASM-low JJN3 exosomes. Inhibition of ASM by amitriptyline, combined with melphalan and bortezomib, increased apoptotic cell death in MM cell lines and on primary CD138+ cells.
In conclusion, this study is the first to identify changes in sphingolipids in plasma of MM patients, where we matched the observed difference to an upregulation of ASM in MM cells. Standard-of-care drugs stimulated ASM expression and production, and cells were able to transfer their resistance to other cells by ASM-rich exosomes. Enzyme inhibition by amitriptyline increased drug efficacy of standard-of-care drugs. This study provides a rational to add ASM-targeting drugs to current combination therapies in MM.
Original languageEnglish
Publication statusPublished - 18 Oct 2019
EventORC day 2019 -
Duration: 18 Oct 201918 Oct 2019

Conference

ConferenceORC day 2019
Period18/10/1918/10/19

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