@article{4298, keywords = {Humans, Glucose, Citric Acid Cycle, Mitochondria, Neoplasms, Aspartic Acid}, author = {Kellen Olszewski and Anthony Barsotti and Xiao-Jiang Feng and Milica Momcilovic and Kevin Liu and Ji-In Kim and Koi Morris and Christophe Lamarque and Jack Gaffney and Xuemei Yu and Jeegar Patel and Joshua Rabinowitz and David Shackelford and Masha Poyurovsky}, title = {Inhibition of glucose transport synergizes with chemical or genetic disruption of mitochondrial metabolism and suppresses TCA cycle-deficient tumors.}, 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.

}, year = {2022}, journal = {Cell Chem Biol}, volume = {29}, pages = {423-435.e10}, month = {2022 Mar 17}, issn = {2451-9448}, doi = {10.1016/j.chembiol.2021.10.007}, language = {eng}, }