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dc.contributor.authorElsaadi, Samah
dc.contributor.authorSteiro, Ida Johnsen
dc.contributor.authorAbdollahi, Pegah
dc.contributor.authorVandsemb, Esten
dc.contributor.authorYang, Rui
dc.contributor.authorSlørdahl, Tobias Schmidt
dc.contributor.authorRø, Torstein Baade
dc.contributor.authorMenu, Eline
dc.contributor.authorSponaas, Anne-Marit
dc.contributor.authorBørset, Magne
dc.description.abstractBackground: Multiple myeloma (MM) is a hematological malignancy characterized by the clonal expansion of plasma cells in the bone marrow. To date, this disease is still incurable and novel therapeutic approaches are required. Phosphoglycerate dehydrogenase (PHGDH) is the frst and rate-limiting enzyme in the de novo serine synthesis path way, and it has been attributed to bortezomib-resistance in MM. Methods: Two diferent PHGDH inhibitors, CBR5884 and NCT-503, were tested against human myeloma cell lines, primary MM cells from patients, and peripheral blood mononuclear cells isolated from healthy donors. The PHGDH inhibitors were then tested in combination with proteasome inhibitors in diferent MM cell lines, including proteas ome-resistant cell lines. Furthermore, we confrmed the efects of PHGDH inhibition through knocking down PHGDH and the efect of NCT-503 in vivo in the 5T33MM mouse model. Results: All the tested myeloma cell lines expressed PHGDH and were sensitive to doses of NCT-503 that were toler ated by peripheral blood mononuclear cells isolated from healthy donors. Upon testing bortezomib in combination with NCT-503, we noticed a clear synergy in several HMCLs. The sensitivity to bortezomib also increased after PHGDH knockdown, mimicking the efect of NCT-503 treatment. Interestingly, targeting PHGDH reduced the intracellular redox capacity of the cells. Furthermore, combination treatment with NCT-503 and bortezomib exhibited a therapeu tic advantage in vivo. Conclusions: Our study shows the therapeutic potential of targeting PHGDH in MM, and suggest it as a way to over come the resistance to proteasome inhibitorsen_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.titleTargeting phosphoglycerate dehydrogenase in multiple myelomaen_US
dc.typePeer revieweden_US
dc.typeJournal articleen_US
dc.source.journalExperimental hematology and oncologyen_US
dc.description.localcode© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativeco The Creative Commons Public Domain Dedication waiver ( zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.en_US

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Navngivelse 4.0 Internasjonal
Except where otherwise noted, this item's license is described as Navngivelse 4.0 Internasjonal