A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance
van der Krift, Felix; Zijlmans, Dick W; Shukla, Rhythm; Javed, Ali; Koukos, Panagiotis I; Schwarz, Laura LE; Timmermans-Sprang, Elpetra Pm; Maas, Peter Em; Gahtory, Digvijay; van den Nieuwboer, Maurits; Mol, Jan A; Strous, Ger J; Bonvin, Alexandre Mjj; van der Stelt, Mario; Veldhuizen, Edwin Ja; Weingarth, Markus; Vermeulen, Michiel; Klumperman, Judith; Maurice, Madelon M
(2023) Life Science Alliance, volume 6, issue 11
(Article)
Abstract
Cancer cells make extensive use of the folate cycle to sustain increased anabolic metabolism. Multiple chemotherapeutic drugs interfere with the folate cycle, including methotrexate and 5-fluorouracil that are commonly applied for the treatment of leukemia and colorectal cancer (CRC), respectively. Despite high success rates, therapy-induced resistance causes relapse at later
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disease stages. Depletion of folylpolyglutamate synthetase (FPGS), which normally promotes intracellular accumulation and activity of natural folates and methotrexate, is linked to methotrexate and 5-fluorouracil resistance and its association with relapse illustrates the need for improved intervention strategies. Here, we describe a novel antifolate (C1) that, like methotrexate, potently inhibits dihydrofolate reductase and downstream one-carbon metabolism. Contrary to methotrexate, C1 displays optimal efficacy in FPGS-deficient contexts, due to decreased competition with intracellular folates for interaction with dihydrofolate reductase. We show that FPGS-deficient patient-derived CRC organoids display enhanced sensitivity to C1, whereas FPGS-high CRC organoids are more sensitive to methotrexate. Our results argue that polyglutamylation-independent antifolates can be applied to exert selective pressure on FPGS-deficient cells during chemotherapy, using a vulnerability created by polyglutamylation deficiency.
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Keywords: Acute lymphoblastic-leukemia, Antiopportunistic infection agents, Cancer-cells, Drug, Folate, Folylpolyglutamate synthetase, Mammalian-cells, Methotrexate, One-carbon metabolism, Resistance
ISSN: 2575-1077
Publisher: Rockefeller University Press
Note: Funding Information: We thank our colleagues of the MM Maurice laboratory and Center for Molecular Medicine for fruitful discussions, feedback, and suggestions; Corlinda ten Brink for assistance during imaging experiments using Cell Microscopy Core equipment; Joep Sprangers and Remco Sleiderink for providing the PiggyBac–CMV–MCS–IRES–mNeonGreen plasmid; Dennis Piet, Sirik Deerenberg, and Tom Speksnijder for the synthesis of C1; Nanda Sprenkels for QC, formulation, and solubility studies on C1; Ingrid Jordens for providing normal colon organoids (P26N) RNA; Michael Hadders, Ingrid Jordens and Joep Sprangers for critical reading of the article; the members of the NWO-TTW user committee for their critical input and discussions. This work is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society (KWF). This work was supported by the Netherlands Organization for Scientific Research (NWO) domain TTW, grant 16083 (J Klumperman, GJ Strous, and JA Mol), Zon-MW VICI grant 91815604 (to MM Maurice), Zon-MW TOP grant 91218050 (MM Maurice), and Gravitation project IMAGINE! (MM Maurice). Publisher Copyright: © 2023 van der Krift et al.
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