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- Health, Toxicology and Mutagenesis
- Plant Science
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
- Ecology
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.