Institute for Cancer Genetics, Columbia University, New York, New York.
Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York.
Cancer Discov. 2022 Nov 2;12(11):2646-2665. doi: 10.1158/2159-8290.CD-22-0010.
Low-intensity maintenance therapy with 6-mercaptopurine (6-MP) limits the occurrence of acute lymphoblastic leukemia (ALL) relapse and is central to the success of multiagent chemotherapy protocols. Activating mutations in the 5'-nucleotidase cytosolic II (NT5C2) gene drive resistance to 6-MP in over 35% of early relapse ALL cases. Here we identify CRCD2 as a first-in-class small-molecule NT5C2 nucleotidase inhibitor broadly active against leukemias bearing highly prevalent relapse-associated mutant forms of NT5C2 in vitro and in vivo. Importantly, CRCD2 treatment also enhanced the cytotoxic activity of 6-MP in NT5C2 wild-type leukemias, leading to the identification of NT5C2 Ser502 phosphorylation as a novel NT5C2-mediated mechanism of 6-MP resistance in this disease. These results uncover an unanticipated role of nongenetic NT5C2 activation as a driver of 6-MP resistance in ALL and demonstrate the potential of NT5C2 inhibitor therapy for enhancing the efficacy of thiopurine maintenance therapy and overcoming resistance at relapse.
Relapse-associated NT5C2 mutations directly contribute to relapse in ALL by driving resistance to chemotherapy with 6-MP. Pharmacologic inhibition of NT5C2 with CRCD2, a first-in-class nucleotidase inhibitor, enhances the cytotoxic effects of 6-MP and effectively reverses thiopurine resistance mediated by genetic and nongenetic mechanisms of NT5C2 activation in ALL. This article is highlighted in the In This Issue feature, p. 2483.
低强度维持治疗用 6-巯基嘌呤（6-MP）可限制急性淋巴细胞白血病（ALL）复发的发生，是多药化疗方案成功的关键。5'-核苷酸酶胞质 II（NT5C2）基因的激活突变导致超过 35%的早期复发 ALL 病例对 6-MP 产生耐药性。在这里，我们确定 CRCD2 是一种新型的小分子 NT5C2 核苷酸酶抑制剂，对体外和体内具有高度普遍复发相关突变形式的 NT5C2 的白血病具有广泛的活性。重要的是，CRCD2 治疗还增强了 NT5C2 野生型白血病中 6-MP 的细胞毒性活性，导致发现 NT5C2 Ser502 磷酸化是该疾病中 NT5C2 介导的 6-MP 耐药的新机制。这些结果揭示了非遗传 NT5C2 激活作为 ALL 中 6-MP 耐药的驱动因素的意外作用，并证明了 NT5C2 抑制剂治疗在增强硫嘌呤维持治疗的疗效和克服复发耐药方面的潜力。
与 ALL 复发相关的 NT5C2 突变通过驱动对 6-MP 的化疗耐药直接导致 ALL 复发。用 CRCD2（一种新型的核苷酸酶抑制剂）抑制 NT5C2 可增强 6-MP 的细胞毒性作用，并有效地逆转由 NT5C2 激活的遗传和非遗传机制介导的硫嘌呤耐药。本文在本期的特色文章中重点介绍，第 2483 页。
