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

  • Cell Chem Biol. 2022 Mar 17;29(3):423-435.e10. doi: 10.1016/j.chembiol.2021.10.007.
Kellen Olszewski  1 ,  Anthony Barsotti  1 ,  Xiao-Jiang Feng  1 ,  Milica Momcilovic  2 ,  Kevin G Liu  1 ,  Ji-In Kim  1 ,  Koi Morris  1 ,  Christophe Lamarque  1 ,  Jack Gaffney  1 ,  Xuemei Yu  1 ,  Jeegar P Patel  1 ,  Joshua D Rabinowitz  3 ,  David B Shackelford  2 ,  Masha V Poyurovsky  4
Affiliations
  • 1. Kadmon Corporation, LLC., New York, NY 10016, USA.
  • 2. Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095, USA.
  • 3. Lewis-Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
  • 4. Kadmon Corporation, LLC., New York, NY 10016, USA. Electronic address: [email protected].
PMID: 34715056 DOI: 10.1016/j.chembiol.2021.10.007
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.

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