Inhibition of glucose transport synergizes with chemical or genetic disruption of mitochondrial metabolism and suppresses TCA cycle-deficient tumors.

TitleInhibition of glucose transport synergizes with chemical or genetic disruption of mitochondrial metabolism and suppresses TCA cycle-deficient tumors.
Publication TypeJournal Article
Year of Publication2021
AuthorsOlszewski, K, Barsotti, A, Feng, X-J, Momcilovic, M, Liu, KG, Kim, J-I, Morris, K, Lamarque, C, Gaffney, J, Yu, X, Patel, JP, Rabinowitz, JD, Shackelford, DB, Poyurovsky, MV
JournalCell Chem Biol
Date Published2021/10/22
ISSN2451-9448
Abstract

Efforts to target glucose metabolism in cancer have been limited by the poor potency and specificity of existing anti-glycolytic agents and a poor understanding of the glucose dependence of cancer subtypes in vivo. Here, we present an extensively characterized series of potent, orally bioavailable inhibitors of the class I glucose transporters (GLUTs). The representative compound KL-11743 specifically blocks glucose metabolism, triggering an acute collapse in NADH pools and a striking accumulation of aspartate, indicating a dramatic shift toward oxidative phosphorylation in the mitochondria. Disrupting mitochondrial metabolism via chemical inhibition of electron transport, deletion of the malate-aspartate shuttle component GOT1, or endogenous mutations in tricarboxylic acid cycle enzymes, causes synthetic lethality with KL-11743. Patient-derived xenograft models of succinate dehydrogenase A (SDHA)-deficient cancers are specifically sensitive to KL-11743, providing direct evidence that TCA cycle-mutant tumors are vulnerable to GLUT inhibitors in vivo.

DOI10.1016/j.chembiol.2021.10.007
Alternate JournalCell Chem Biol
PubMed ID34715056