Pharmacologic Inhibition of NT5C2 Reverses Genetic and Nongenetic Drivers of 6-MP Resistance in Acute Lymphoblastic Leukemia
Reglero, Clara (Columbia University)
Dieck, Chelsea L. (Columbia University)
Zask, Arie (Columbia University)
Forouhar, Farhad (Columbia University)
Laurent, Anouchka (Columbia University)
W.Lin, Wen-Hsuan (Columbia University Medical Center)
Albero, Robert (Columbia University)
Miller, Hannah I. (Columbia University)
Ma, Cindy (Columbia University)
Gastier-Foster, Julie M. (Baylor College of Medicine (Houston, Estats Units d'Amèrica))
Loh, Mignon L. (University of Washington)
Tong, Liang (Columbia University)
Stockwell, Brent (Columbia University)
Palomero, Teresa (Columbia University)
Ferrando, Adolfo A. (Columbia University)

Date:	2022
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. 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.
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Language:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Subject:	Acute lymphoblastic leukemia ; ALL ; Relapse ; Chemotherapy resistance ; NT5C2 ; Targeted therapy ; Nucleotidase inhibitor
Published in:	Cancer Discovery, Vol. 12 Núm. 11 (November 2022) , p. 2646-2665, ISSN 2159-8290

DOI: 10.1158/2159-8290.CD-22-0010
PMID: 35984649

Postprint 55 p, 2.7 MB

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