TitleInhibition of glucose transport synergizes with chemical or genetic disruption of mitochondrial metabolism and suppresses TCA cycle-deficient tumors.
Publication TypeJournal Article
Year of Publication2022
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 Published2022 03 17
KeywordsAspartic Acid, Citric Acid Cycle, Glucose, Humans, Mitochondria, Neoplasms

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.

Alternate JournalCell Chem Biol
PubMed ID34715056