Targeting phosphoglycerate dehydrogenase in multiple myeloma
Elsaadi, Samah; Steiro, Ida Johnsen; Abdollahi, Pegah; Vandsemb, Esten; Yang, Rui; Slørdahl, Tobias Schmidt; Rø, Torstein Baade; Menu, Eline; Sponaas, Anne-Marit; Børset, Magne
Peer reviewed, Journal article
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Date
2021Metadata
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- Institutt for klinisk og molekylær medisin [3690]
- Publikasjoner fra CRIStin - NTNU [39956]
- St. Olavs hospital [2697]
Original version
10.1186/s40164-020-00196-wAbstract
Background: 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 inhibitors