Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas
Open Access
- 26 August 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cellular and Molecular Life Sciences
- Vol. 78 (4), 1837-1851
- https://doi.org/10.1007/s00018-020-03620-w
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.Keywords
Funding Information
- the Wendy Walk Foundation
- Singapore Ministry of Health’s National Medical Research Council (NMRC/STaR/0021/2014)
- Singapore Ministry of Education (MOE2013-T2-2-150)
- Singapore Ministry of Health’s National Medical Research Council (NMRC/CG/012/2013, CGAug16M005)
- National Institutes of Health (R01 CA200992-04)
- Karyopharm Therapeutics
- Nanyang Technological University (NTU presidential postdoctoral fellowship)
This publication has 49 references indexed in Scilit:
- The Cancer Genome Atlas Pan-Cancer analysis projectNature Genetics, 2013
- The Genotype-Tissue Expression (GTEx) projectNature Genetics, 2013
- HSF1 Drives a Transcriptional Program Distinct from Heat Shock to Support Highly Malignant Human CancersCell, 2012
- Immuno- and Constitutive Proteasome Crystal Structures Reveal Differences in Substrate and Inhibitor SpecificityCell, 2012
- Incidence of Sarcoma Histotypes and Molecular Subtypes in a Prospective Epidemiological Study with Central Pathology Review and Molecular TestingPLOS ONE, 2011
- A Protein Inventory of Human Ribosome Biogenesis Reveals an Essential Function of Exportin 5 in 60S Subunit ExportPLoS Biology, 2010
- Peripheral neuropathy during bortezomib treatment of multiple myeloma: a review of recent studiesLeukemia & Lymphoma, 2010
- Disruption of crosstalk between the fatty acid synthesis and proteasome pathways enhances unfolded protein response signaling and cell deathMolecular Cancer Therapeutics, 2008
- Antitumor Activity of PR-171, a Novel Irreversible Inhibitor of the ProteasomeCancer Research, 2007
- Synergistic Induction of Oxidative Injury and Apoptosis in Human Multiple Myeloma Cells by the Proteasome Inhibitor Bortezomib and Histone Deacetylase InhibitorsClinical Cancer Research, 2004