journal contribution
posted on 2023-04-04, 00:23 authored by Clara Reglero, Chelsea L. Dieck, Arie Zask, Farhad Forouhar, Anouchka P. Laurent, Wen-Hsuan W. Lin, Robert Albero, Hannah I. Miller, Cindy Ma, Julie M. Gastier-Foster, Mignon L. Loh, Liang Tong, Brent R. Stockwell, Teresa Palomero, Adolfo A. Ferrando Supplementary Figure from Pharmacologic Inhibition of NT5C2 Reverses Genetic and Nongenetic Drivers of 6-MP Resistance in Acute Lymphoblastic Leukemia
Funding
Chemotherapy Foundation (The Chemotherapy Foundation)
National Cancer Institute (NCI)
United States Department of Health and Human Services
Find out more...Leukemia and Lymphoma Society (LLS)
Alex’s Lemonade Stand Foundation for Childhood Cancer (ALSF)
Columbia University (Columbia)
History
ARTICLE ABSTRACT
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
