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- Title
Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas.
- Authors
Jeitany, Maya; Prabhu, Aishvaryaa; Dakle, Pushkar; Pathak, Elina; Madan, Vikas; Kanojia, Deepika; Mukundan, Vineeth; Jiang, Yan Yi; Landesman, Yosef; Tam, Wai Leong; Kappei, Dennis; Koeffler, H. Phillip
- Abstract
Proteasome inhibitors, such as bortezomib and carfilzomib, have shown efficacy in anti-cancer therapy in hematological diseases but not in solid cancers. Here, we found that liposarcomas (LPS) are susceptible to proteasome inhibition, and identified drugs that synergize with carfilzomib, such as selinexor, an inhibitor of XPO1-mediated nuclear export. Through quantitative nuclear protein profiling and phospho-kinase arrays, we identified potential mode of actions of this combination, including interference with ribosome biogenesis and inhibition of pro-survival kinase PRAS40. Furthermore, by assessing global protein levels changes, FADS2, a key enzyme regulating fatty acids synthesis, was found down-regulated after proteasome inhibition. Interestingly, SC26196, an inhibitor of FADS2, synergized with carfilzomib. Finally, to identify further combinational options, we performed high-throughput drug screening and uncovered novel drug interactions with carfilzomib. For instance, cyclosporin A, a known immunosuppressive agent, enhanced carfilzomib's efficacy in vitro and in vivo. Altogether, these results demonstrate that carfilzomib and its combinations could be repurposed for LPS clinical management.
- Subjects
LIPOSARCOMA; CYCLOSPORINE; NUCLEAR proteins; PROTEASOME inhibitors; IMMUNOSUPPRESSIVE agents; PROTEASOMES; RIBOSOMES
- Publication
Cellular & Molecular Life Sciences, 2021, Vol 78, Issue 4, p1837
- ISSN
1420-682X
- Publication type
Article
- DOI
10.1007/s00018-020-03620-w