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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 
Keywords: Combinational therapies
Proteasome inhibitors
Issue Date: 26-Aug-2020
Publisher: Springer Science and Business Media Deutschland GmbH
Citation: 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 (2020-08-26). Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas. Cellular and Molecular Life Sciences 78 (4) : 1837-1851. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
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. © 2020, The Author(s).
Source Title: Cellular and Molecular Life Sciences
ISSN: 1420-682X
DOI: 10.1007/s00018-020-03620-w
Rights: Attribution 4.0 International
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