Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Molecular Biology and Oncode Institute, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
Life Sci Alliance. 2023 Aug 17;6(11). doi: 10.26508/lsa.202302058. Print 2023 Nov.
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.
癌细胞广泛利用叶酸循环来维持增加的合成代谢。多种化疗药物干扰叶酸循环，包括甲氨蝶呤和 5-氟尿嘧啶，分别常用于治疗白血病和结直肠癌 (CRC)。尽管治疗成功率很高，但治疗诱导的耐药性导致疾病后期复发。叶酸多聚谷氨酸合成酶 (FPGS) 的耗竭通常会促进天然叶酸和甲氨蝶呤在细胞内的积累和活性，与甲氨蝶呤和 5-氟尿嘧啶耐药性有关，其与复发的关联表明需要改进干预策略。在这里，我们描述了一种新型的叶酸类似物 (C1)，它像甲氨蝶呤一样，强烈抑制二氢叶酸还原酶和下游的一碳代谢。与甲氨蝶呤不同，C1 在 FPGS 缺陷的情况下显示出最佳的疗效，因为它与二氢叶酸还原酶的相互作用减少了与细胞内叶酸的竞争。我们表明，FPGS 缺陷的患者来源的 CRC 类器官对 C1 显示出增强的敏感性，而 FPGS 高的 CRC 类器官对甲氨蝶呤更敏感。我们的结果表明，多聚谷氨酸化非依赖性叶酸类似物可在化疗期间用于对 FPGS 缺陷细胞施加选择性压力，利用多聚谷氨酸化缺陷产生的脆弱性。
