| Autor: |
Adolfo A. Ferrando, Teresa Palomero, Brent R. Stockwell, Liang Tong, Mignon L. Loh, Julie M. Gastier-Foster, Cindy Ma, Hannah I. Miller, Robert Albero, Wen-Hsuan W. Lin, Anouchka P. Laurent, Farhad Forouhar, Arie Zask, Chelsea L. Dieck, Clara Reglero |
| Rok vydání: |
2023 |
| ISSN: |
2159-8290 |
| DOI: |
10.1158/2159-8290.c.6549792.v1 |
| Popis: |
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.Significance: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 |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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