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

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.

Automated summary

In this study, researchers developed a series of potent, orally bioavailable inhibitors of class I glucose transporters (GLUTs). The representative compound KL-11743 specifically blocks glucose metabolism, leading to an increase in oxidative phosphorylation in the mitochondria. Disrupting mitochondrial metabolism in combination with KL-11743 causes synthetic lethality, and patient-derived xenograft models demonstrate the vulnerability of succinate dehydrogenase A (SDHA)-deficient cancers to GLUT inhibitors.