Abstract C005: NT5C2 small molecule inhibitor for the reversal of 6-MP resistance in acute lymphoblastic leukemia

Le résumé fourni par la source

Abstract Activating mutations in the cytosolic 5’-nucleotidase II (NT5C2) gene drive resistance to chemotherapy with 6-mercaptopurine (6-MP) in acute lymphoblastic leukemia (ALL) highlighting NT5C2 as a potential therapeutic target. In efforts to reverse 6-MP therapy resistance, we performed high throughput screens to identify small molecule inhibitors of NT5C2. Using a high throughput malachite-green based NT5C2 nucleotidase assay, we identified HTP_2 as a lead compound with low micromolar inhibitory activity against NT5C2 R367Q mutant recombinant protein. HTP_2 reverses 6-MP resistance in Nt5c2+/R367Qmutant mouse lymphoblasts and NT5C2 R29Q mutant expressing human cell lines. In addition, HTP_2 treatment results in increased sensitivity to 6-MP therapy in NT5C2 wild-type cells, highlighting the role of wild-type NT5C2 activity in the clearance of 6-MP. These results support a potential therapeutic use for NT5C2 inhibitors in potentiating the effects of 6-MP based chemotherapy in NT5C2 wild-type cells as well as NT5C2 mutant cells. Overall, this study presents a framework for the development of a NT5C2 inhibitor for the reversal of 6-MP resistance in relapsed ALL patients. Citation Format: Chelsea Dieck, Clara Reglero-Gomez, Arie Zask, Brent Stockwell, Adolfo Ferrando. NT5C2 small molecule inhibitor for the reversal of 6-MP resistance in acute lymphoblastic leukemia [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C005. doi:10.1158/1535-7163.TARG-19-C005

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.