TY - JOUR
T1 - Inhibition of glucose transport synergizes with chemical or genetic disruption of mitochondrial metabolism and suppresses TCA cycle-deficient tumors
AU - Olszewski, Kellen
AU - Barsotti, Anthony
AU - Feng, Xiao Jiang
AU - Momcilovic, Milica
AU - Liu, Kevin G.
AU - Kim, Ji In
AU - Morris, Koi
AU - Lamarque, Christophe
AU - Gaffney, Jack
AU - Yu, Xuemei
AU - Patel, Jeegar P.
AU - Rabinowitz, Joshua D.
AU - Shackelford, David B.
AU - Poyurovsky, Masha V.
N1 - Publisher Copyright:
© 2021 The Author(s)
PY - 2022/3/17
Y1 - 2022/3/17
N2 - 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.
AB - 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.
KW - GLUT inhibitor
KW - PDX models
KW - electron transport chain inhibitors
KW - glycolysis
KW - imaging
KW - malate-aspartate shuttle
KW - mitochondrial inhibitors
KW - pharmacology
KW - redox biology
KW - toxicology
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U2 - 10.1016/j.chembiol.2021.10.007
DO - 10.1016/j.chembiol.2021.10.007
M3 - Article
C2 - 34715056
AN - SCOPUS:85122063811
SN - 2451-9456
VL - 29
SP - 423-435.e10
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 3
ER -