2. Academic Validation
  3. Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas

Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas

  • Cell Mol Life Sci. 2021 Feb;78(4):1837-1851. doi: 10.1007/s00018-020-03620-w.
Maya Jeitany 1 2,  Aishvaryaa Prabhu 3,  Pushkar Dakle 3,  Elina Pathak 3 4,  Vikas Madan 3,  Deepika Kanojia 3,  Vineeth Mukundan 3,  Yan Yi Jiang 3,  Yosef Landesman 5,  Wai Leong Tam 3 4,  Dennis Kappei 3 6,  H Phillip Koeffler 3 7 8
Affiliations

Affiliations

  • 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. maya.jeitany@gmail.com.
  • 2 School of Biological Sciences, Nanyang Technological University, Singapore, Singapore. maya.jeitany@gmail.com.
  • 3 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • 4 Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • 5 Karyopharm Therapeutics, Newton, MA, USA.
  • 6 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 7 Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA, USA.
  • 8 Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Hospital, Singapore, Singapore.
PMID: 32851475 DOI: 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

Combinational therapies; Liposarcoma; Proteasome inhibitors.

Figures
Products