{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T03:23:54Z","timestamp":1793071434388,"version":"4.5.0"},"reference-count":77,"publisher":"Life Science Alliance, LLC","issue":"11","license":[{"start":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T00:00:00Z","timestamp":1692230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021821","name":"Oncode Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100021821","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["TTW 16083"],"award-info":[{"award-number":["TTW 16083"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["VICI 91815604"],"award-info":[{"award-number":["VICI 91815604"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["TOP 91218050"],"award-info":[{"award-number":["TOP 91218050"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["Gravitation IMAGINE!"],"award-info":[{"award-number":["Gravitation IMAGINE!"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["life-science-alliance.org"],"crossmark-restriction":true},"short-container-title":["Life Sci. Alliance"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.26508\/lsa.202302058","type":"journal-article","created":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T12:01:35Z","timestamp":1692360095000},"page":"e202302058","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance"],"prefix":"10.26508","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3859-8776","authenticated-orcid":true,"given":"Felix","family":"van der Krift","sequence":"first","affiliation":[{"name":"Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1527-1834","authenticated-orcid":true,"given":"Dick W","family":"Zijlmans","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Oncode Institute, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhythm","family":"Shukla","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04pp8hn57","id-type":"ROR","asserted-by":"publisher"}],"name":"NMR Spectroscopy, Bijvoet Centre for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University","place":[", Utrecht, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4592-4445","authenticated-orcid":true,"given":"Ali","family":"Javed","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04pp8hn57","id-type":"ROR","asserted-by":"publisher"}],"name":"NMR Spectroscopy, Bijvoet Centre for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University","place":[", Utrecht, The Netherlands"]},{"id":[{"id":"https:\/\/ror.org\/04pp8hn57","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Utrecht University","place":[", Utrecht, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis I","family":"Koukos","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04pp8hn57","id-type":"ROR","asserted-by":"publisher"}],"name":"Computational Structural Biology, Bijvoet Centre for Biomolecular Research, Faculty of Science, Department of Chemistry, Utrecht University","place":[", Utrecht, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura LE","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3251-2014","authenticated-orcid":true,"given":"Elpetra PM","family":"Timmermans-Sprang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04pp8hn57","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Sciences of Companion Animals, Utrecht University","place":[", Utrecht, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter EM","family":"Maas","sequence":"additional","affiliation":[{"name":"Specs Compound Handling B.V., Zoetermeer, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Digvijay","family":"Gahtory","sequence":"additional","affiliation":[{"name":"BIMINI Biotech B.V., Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurits","family":"van den Nieuwboer","sequence":"additional","affiliation":[{"name":"BIMINI Biotech B.V., Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan A","family":"Mol","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04pp8hn57","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Sciences of Companion Animals, Utrecht University","place":[", Utrecht, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ger J","family":"Strous","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7369-1322","authenticated-orcid":true,"given":"Alexandre MJJ","family":"Bonvin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04pp8hn57","id-type":"ROR","asserted-by":"publisher"}],"name":"Computational Structural Biology, Bijvoet Centre for Biomolecular Research, Faculty of Science, Department of Chemistry, Utrecht University","place":[", Utrecht, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"van der Stelt","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Oncode Institute, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9133-7965","authenticated-orcid":true,"given":"Edwin JA","family":"Veldhuizen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04pp8hn57","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Utrecht University","place":[", Utrecht, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0831-8673","authenticated-orcid":true,"given":"Markus","family":"Weingarth","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04pp8hn57","id-type":"ROR","asserted-by":"publisher"}],"name":"NMR Spectroscopy, Bijvoet Centre for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University","place":[", Utrecht, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiel","family":"Vermeulen","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Oncode Institute, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Klumperman","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6885-5361","authenticated-orcid":true,"given":"Madelon M","family":"Maurice","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"12380","published-online":{"date-parts":[[2023,8,17]]},"reference":[{"key":"2023082309504631000_6.11.e202302058.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmgm.2010.11.004"},{"key":"2023082309504631000_6.11.e202302058.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2015.05.008"},{"key":"2023082309504631000_6.11.e202302058.3","doi-asserted-by":"publisher","DOI":"10.3945\/jn.114.206599"},{"key":"2023082309504631000_6.11.e202302058.4","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2185"},{"key":"2023082309504631000_6.11.e202302058.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.03.053"},{"key":"2023082309504631000_6.11.e202302058.6","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/28.1.235"},{"key":"2023082309504631000_6.11.e202302058.7","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2676"},{"key":"2023082309504631000_6.11.e202302058.8","doi-asserted-by":"publisher","DOI":"10.3390\/metabo13020151"},{"key":"2023082309504631000_6.11.e202302058.9","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-07-0449"},{"key":"2023082309504631000_6.11.e202302058.10","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444904030422"},{"key":"2023082309504631000_6.11.e202302058.11","doi-asserted-by":"publisher","DOI":"10.1021\/acsptsci.0c00223"},{"key":"2023082309504631000_6.11.e202302058.12","doi-asserted-by":"publisher","DOI":"10.1124\/mol.119.117937"},{"key":"2023082309504631000_6.11.e202302058.13","doi-asserted-by":"publisher","DOI":"10.1021\/ja026939x"},{"key":"2023082309504631000_6.11.e202302058.14","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PONE.0231588"},{"key":"2023082309504631000_6.11.e202302058.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.08.009"},{"key":"2023082309504631000_6.11.e202302058.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.05.043"},{"key":"2023082309504631000_6.11.e202302058.17","first-page":"3190","article-title":"Polyglutamylation, an important element in methotrexate cytotoxicity and selectivity in tumor versus murine granulocytic progenitor cells in vitro","volume":"44","author":"Fabre","year":"1984","journal-title":"Cancer Res"},{"key":"2023082309504631000_6.11.e202302058.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2003.10.069"},{"key":"2023082309504631000_6.11.e202302058.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2008.12.026"},{"key":"2023082309504631000_6.11.e202302058.20","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.088"},{"key":"2023082309504631000_6.11.e202302058.21","doi-asserted-by":"publisher","DOI":"10.2174\/187152007781668724"},{"key":"2023082309504631000_6.11.e202302058.22","doi-asserted-by":"publisher","DOI":"10.2174\/187152008783497064"},{"key":"2023082309504631000_6.11.e202302058.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1186-3"},{"key":"2023082309504631000_6.11.e202302058.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.10.029"},{"key":"2023082309504631000_6.11.e202302058.25","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/18.suppl_1.S96"},{"key":"2023082309504631000_6.11.e202302058.26","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3590"},{"key":"2023082309504631000_6.11.e202302058.27","first-page":"761","article-title":"Multiple mechanisms of resistance to polyglutamatable and lipophilic antifolates in mammalian cells: Role of increased folylpolyglutamylation, expanded folate pools, and intralysosomal drug sequestration","volume":"55","author":"Jansen","year":"1999","journal-title":"Mol Pharmacol"},{"key":"2023082309504631000_6.11.e202302058.28","doi-asserted-by":"publisher","DOI":"10.1021\/ja00214a001"},{"key":"2023082309504631000_6.11.e202302058.29","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2013.579"},{"key":"2023082309504631000_6.11.e202302058.30","doi-asserted-by":"publisher","DOI":"10.1021\/ACS.JCIM.1C00796"},{"key":"2023082309504631000_6.11.e202302058.31","doi-asserted-by":"publisher","DOI":"10.1021\/bi400852h"},{"key":"2023082309504631000_6.11.e202302058.32","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.593244"},{"key":"2023082309504631000_6.11.e202302058.33","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019002220"},{"key":"2023082309504631000_6.11.e202302058.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.09.015"},{"key":"2023082309504631000_6.11.e202302058.35","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.10829"},{"key":"2023082309504631000_6.11.e202302058.36","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1074"},{"key":"2023082309504631000_6.11.e202302058.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-3002-5"},{"key":"2023082309504631000_6.11.e202302058.38","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20199232"},{"key":"2023082309504631000_6.11.e202302058.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2018.07.001"},{"key":"2023082309504631000_6.11.e202302058.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41596&ndash;019&ndash;0128&ndash;8"},{"key":"2023082309504631000_6.11.e202302058.41","doi-asserted-by":"publisher","DOI":"10.1126\/science.1233606"},{"key":"2023082309504631000_6.11.e202302058.42","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2008.251"},{"key":"2023082309504631000_6.11.e202302058.43","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4128"},{"key":"2023082309504631000_6.11.e202302058.44","doi-asserted-by":"publisher","DOI":"10.1242\/bio.042812"},{"key":"2023082309504631000_6.11.e202302058.45","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(20)80592-4"},{"key":"2023082309504631000_6.11.e202302058.46","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1106"},{"key":"2023082309504631000_6.11.e202302058.47","doi-asserted-by":"publisher","DOI":"10.1021\/JM00156A029"},{"key":"2023082309504631000_6.11.e202302058.48","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.261"},{"key":"2023082309504631000_6.11.e202302058.49","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.5b00654"},{"key":"2023082309504631000_6.11.e202302058.50","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"2023082309504631000_6.11.e202302058.51","doi-asserted-by":"publisher","DOI":"10.1182\/BLOOD.V93.5.1677"},{"key":"2023082309504631000_6.11.e202302058.52","doi-asserted-by":"publisher","DOI":"10.1126\/science.1255784"},{"key":"2023082309504631000_6.11.e202302058.53","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444904011679"},{"key":"2023082309504631000_6.11.e202302058.54","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2004.042713"},{"key":"2023082309504631000_6.11.e202302058.55","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-08-173799"},{"key":"2023082309504631000_6.11.e202302058.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2021.104169"},{"key":"2023082309504631000_6.11.e202302058.57","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-023-01525-1"},{"key":"2023082309504631000_6.11.e202302058.58","doi-asserted-by":"publisher","DOI":"10.1038\/S41573-021-00339-6"},{"key":"2023082309504631000_6.11.e202302058.59","doi-asserted-by":"publisher","DOI":"10.3109\/02841869509094036"},{"key":"2023082309504631000_6.11.e202302058.60","doi-asserted-by":"publisher","DOI":"10.1037\/\/0033-295X.84.4.327"},{"key":"2023082309504631000_6.11.e202302058.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.03.053"},{"key":"2023082309504631000_6.11.e202302058.62","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.926210"},{"key":"2023082309504631000_6.11.e202302058.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2015.09.014"},{"key":"2023082309504631000_6.11.e202302058.64","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.0c00025"},{"key":"2023082309504631000_6.11.e202302058.65","doi-asserted-by":"publisher","DOI":"10.1021\/ci00057a005"},{"key":"2023082309504631000_6.11.e202302058.66","doi-asserted-by":"publisher","DOI":"10.1021\/ci00062a008"},{"key":"2023082309504631000_6.11.e202302058.67","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2014.51"},{"key":"2023082309504631000_6.11.e202302058.68","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29919"},{"key":"2023082309504631000_6.11.e202302058.69","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.81"},{"key":"2023082309504631000_6.11.e202302058.70","doi-asserted-by":"publisher","DOI":"10.1038\/S41598-020-69059-Y"},{"key":"2023082309504631000_6.11.e202302058.71","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-021-01189-2"},{"key":"2023082309504631000_6.11.e202302058.72","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206946"},{"key":"2023082309504631000_6.11.e202302058.73","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(01)00532-9"},{"key":"2023082309504631000_6.11.e202302058.74","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M807665200"},{"key":"2023082309504631000_6.11.e202302058.75","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-nutr-072610-145133"},{"key":"2023082309504631000_6.11.e202302058.76","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20181965"},{"key":"2023082309504631000_6.11.e202302058.77","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.09.041"}],"container-title":["Life Science Alliance"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.26508\/lsa.202302058","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T09:08:10Z","timestamp":1704877690000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.life-science-alliance.org\/lookup\/doi\/10.26508\/lsa.202302058"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,17]]},"references-count":77,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,8,17]]},"published-print":{"date-parts":[[2023,11]]}},"alternative-id":["10.26508\/lsa.202302058"],"URL":"https:\/\/doi.org\/10.26508\/lsa.202302058","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.02.26.530079","asserted-by":"object"}]},"ISSN":["2575-1077"],"issn-type":[{"value":"2575-1077","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,17]]}}}