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

Kellen Olszewski, Anthony Barsotti, Xiao Jiang Feng, Milica Momcilovic, Kevin G. Liu, Ji In Kim, Koi Morris, Christophe Lamarque, Jack Gaffney, Xuemei Yu, Jeegar P. Patel, Joshua D. Rabinowitz, David B. Shackelford, Masha V. Poyurovsky

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)423-435.e10
JournalCell Chemical Biology
Volume29
Issue number3
DOIs
StatePublished - Mar 17 2022

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Keywords

  • GLUT inhibitor
  • PDX models
  • electron transport chain inhibitors
  • glycolysis
  • imaging
  • malate-aspartate shuttle
  • mitochondrial inhibitors
  • pharmacology
  • redox biology
  • toxicology

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