Dual Covalent Inhibition of PKM and IMPDH Targets Metabolism in Cutaneous Metastatic Melanoma.

Autor:	Zerhouni M; Université Côte d'azur, Nice, France.; Inserm U1065, C3M, Team 2, Nice, France.; Inserm U1065, C3M, Team 12, Nice, France., Martin AR; Université Côte d'azur, Nice, France.; Institut de Chimie de Nice UMR 7272, Nice, France., Furstoss N; Université Côte d'azur, Nice, France.; Inserm U1065, C3M, Team 2, Nice, France., Gutierrez VS; Université Côte d'azur, Nice, France.; Institut de Chimie de Nice UMR 7272, Nice, France., Jaune E; Université Côte d'azur, Nice, France.; Inserm U1065, C3M, Team 12, Nice, France., Tekaya N; Université Côte d'azur, Nice, France.; Inserm U1065, C3M, Team 12, Nice, France., Beranger GE; Université Côte d'azur, Nice, France.; Inserm U1065, C3M, Team 12, Nice, France., Abbe P; Université Côte d'azur, Nice, France.; Inserm U1065, C3M, Team 12, Nice, France., Regazzetti C; Université Côte d'azur, Nice, France.; Inserm U1065, C3M, Team 12, Nice, France., Amdouni H; Université Côte d'azur, Nice, France.; Institut de Chimie de Nice UMR 7272, Nice, France., Driowya M; Université Côte d'azur, Nice, France.; Institut de Chimie de Nice UMR 7272, Nice, France., Dubreuil P; CRCM, Team Signalisation, Hématopoïèse et Mécanismes de l'Oncogenèse, Marseille, France., Luciano F; Université Côte d'azur, Nice, France.; Inserm U1065, C3M, Team 2, Nice, France., Jacquel A; Université Côte d'azur, Nice, France.; Inserm U1065, C3M, Team 2, Nice, France., Tulic MK; Université Côte d'azur, Nice, France.; Inserm U1065, C3M, Team 2, Nice, France., Cluzeau T; Université Côte d'azur, Nice, France.; Inserm U1065, C3M, Team 2, Nice, France.; CHU de Nice, Nice, France., O'Hara BP; Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois., Ben-Sahra I; Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois., Passeron T; Université Côte d'azur, Nice, France.; Inserm U1065, C3M, Team 12, Nice, France.; CHU de Nice, Nice, France., Benhida R; Institut de Chimie de Nice UMR 7272, Nice, France., Robert G; Université Côte d'azur, Nice, France.; Inserm U1065, C3M, Team 2, Nice, France., Auberger P; Université Côte d'azur, Nice, France. srocchi@unice.fr auberger@unice.fr.; Inserm U1065, C3M, Team 2, Nice, France., Rocchi S; Université Côte d'azur, Nice, France. srocchi@unice.fr auberger@unice.fr.; Inserm U1065, C3M, Team 12, Nice, France.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2021 Jul 15; Vol. 81 (14), pp. 3806-3821. Date of Electronic Publication: 2021 Jun 07.
DOI:	10.1158/0008-5472.CAN-20-2114
Abstrakt:	Overcoming acquired drug resistance is a primary challenge in cancer treatment. Notably, more than 50% of patients with BRAF V600E cutaneous metastatic melanoma (CMM) eventually develop resistance to BRAF inhibitors. Resistant cells undergo metabolic reprogramming that profoundly influences therapeutic response and promotes tumor progression. Uncovering metabolic vulnerabilities could help suppress CMM tumor growth and overcome drug resistance. Here we identified a drug, HA344, that concomitantly targets two distinct metabolic hubs in cancer cells. HA344 inhibited the final and rate-limiting step of glycolysis through its covalent binding to the pyruvate kinase M2 (PKM2) enzyme, and it concurrently blocked the activity of inosine monophosphate dehydrogenase, the rate-limiting enzyme of de novo guanylate synthesis. As a consequence, HA344 efficiently targeted vemurafenib-sensitive and vemurafenib-resistant CMM cells and impaired CMM xenograft tumor growth in mice. In addition, HA344 acted synergistically with BRAF inhibitors on CMM cell lines in vitro . Thus, the mechanism of action of HA344 provides potential therapeutic avenues for patients with CMM and a broad range of different cancers. SIGNIFICANCE: Glycolytic and purine synthesis pathways are often deregulated in therapy-resistant tumors and can be targeted by the covalent inhibitor described in this study, suggesting its broad application for overcoming resistance in cancer. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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