A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance

Felix van der Krift; Dick W Zijlmans; Rhythm Shukla; Ali Javed; Panagiotis I Koukos; Laura LE Schwarz; Elpetra Pm Timmermans-Sprang; Peter Em Maas; Digvijay Gahtory; Maurits van den Nieuwboer; Jan A Mol; Ger J Strous; Alexandre Mjj Bonvin; Mario van der Stelt; Edwin Ja Veldhuizen; Markus Weingarth; Michiel Vermeulen; Judith Klumperman; Madelon M Maurice

doi:10.26508/lsa.202302058

A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance

Felix van der Krift, Dick W Zijlmans, Rhythm Shukla, Ali Javed, Panagiotis I Koukos, Laura LE Schwarz, Elpetra Pm Timmermans-Sprang, Peter Em Maas, Digvijay Gahtory, Maurits van den Nieuwboer, Jan A Mol, Ger J Strous, Alexandre Mjj Bonvin, Mario van der Stelt, Edwin Ja Veldhuizen, Markus Weingarth, Michiel Vermeulen, Judith Klumperman, Madelon M Maurice^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 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.

Original language	English
Article number	e202302058
Number of pages	19
Journal	Life Science Alliance
Volume	6
Issue number	11
Early online date	17 Aug 2023
DOIs	https://doi.org/10.26508/lsa.202302058
Publication status	Published - 1 Nov 2023

Bibliographical 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.

Keywords

Acute lymphoblastic-leukemia
Antiopportunistic infection agents
Cancer-cells
Drug
Folate
Folylpolyglutamate synthetase
Mammalian-cells
Methotrexate
One-carbon metabolism
Resistance

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.26508/lsa.202302058Licence: CC BY

e202302058.fullFinal published version, 2.92 MBLicence: CC BY

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van der Krift, F., Zijlmans, D. W., Shukla, R., Javed, A., Koukos, P. I., Schwarz, L. LE., Timmermans-Sprang, E. P., Maas, P. E., Gahtory, D., van den Nieuwboer, M., Mol, J. A., Strous, G. J., Bonvin, A. M., van der Stelt, M., Veldhuizen, E. J., Weingarth, M., Vermeulen, M., Klumperman, J., & Maurice, M. M. (2023). A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance. Life Science Alliance, 6(11), Article e202302058. https://doi.org/10.26508/lsa.202302058

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title = "A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance",

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 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.",

keywords = "Acute lymphoblastic-leukemia, Antiopportunistic infection agents, Cancer-cells, Drug, Folate, Folylpolyglutamate synthetase, Mammalian-cells, Methotrexate, One-carbon metabolism, Resistance",

author = "\{van der Krift\}, Felix and Zijlmans, \{Dick W\} and Rhythm Shukla and Ali Javed and Koukos, \{Panagiotis I\} and Schwarz, \{Laura LE\} and Timmermans-Sprang, \{Elpetra Pm\} and Maas, \{Peter Em\} and Digvijay Gahtory and \{van den Nieuwboer\}, Maurits and Mol, \{Jan A\} and Strous, \{Ger J\} and Bonvin, \{Alexandre Mjj\} and \{van der Stelt\}, Mario and Veldhuizen, \{Edwin Ja\} and Markus Weingarth and Michiel Vermeulen and Judith Klumperman and Maurice, \{Madelon M\}",

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: {\textcopyright} 2023 van der Krift et al.",

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doi = "10.26508/lsa.202302058",

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van der Krift, F, Zijlmans, DW, Shukla, R, Javed, A, Koukos, PI, Schwarz, LLE, Timmermans-Sprang, EP, Maas, PE, Gahtory, D, van den Nieuwboer, M, Mol, JA, Strous, GJ, Bonvin, AM, van der Stelt, M, Veldhuizen, EJ , Weingarth, M, Vermeulen, M, Klumperman, J & Maurice, MM 2023, 'A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance', Life Science Alliance, vol. 6, no. 11, e202302058. https://doi.org/10.26508/lsa.202302058

TY - JOUR

T1 - A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance

AU - van der Krift, Felix

AU - Zijlmans, Dick W

AU - Shukla, Rhythm

AU - Javed, Ali

AU - Koukos, Panagiotis I

AU - Schwarz, Laura LE

AU - Timmermans-Sprang, Elpetra Pm

AU - Maas, Peter Em

AU - Gahtory, Digvijay

AU - van den Nieuwboer, Maurits

AU - Mol, Jan A

AU - Strous, Ger J

AU - Bonvin, Alexandre Mjj

AU - van der Stelt, Mario

AU - Veldhuizen, Edwin Ja

AU - Weingarth, Markus

AU - Vermeulen, Michiel

AU - Klumperman, Judith

AU - Maurice, Madelon M

N1 - 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.

PY - 2023/11/1

Y1 - 2023/11/1

N2 - 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 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.

AB - 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 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.

KW - Acute lymphoblastic-leukemia

KW - Antiopportunistic infection agents

KW - Cancer-cells

KW - Drug

KW - Folate

KW - Folylpolyglutamate synthetase

KW - Mammalian-cells

KW - Methotrexate

KW - One-carbon metabolism

KW - Resistance

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DO - 10.26508/lsa.202302058

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SN - 2575-1077

VL - 6

JO - Life Science Alliance

JF - Life Science Alliance

IS - 11

M1 - e202302058

ER -

A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance

Abstract

Bibliographical note

Keywords

UN SDGs

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