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Targeted Inhibition of EGFR and Glutaminase Induces Metabolic Crisis in EGFR Mutant Lung Cancer.

Abstract
Cancer cells exhibit increased use of nutrients, including glucose and glutamine, to support the bioenergetic and biosynthetic demands of proliferation. We tested the small-molecule inhibitor of glutaminase CB-839 in combination with erlotinib on epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) as a therapeutic strategy to simultaneously impair cancer glucose and glutamine utilization and thereby suppress tumor growth. Here, we show that CB-839 cooperates with erlotinib to drive energetic stress and activate the AMP-activated protein kinase (AMPK) pathway in EGFR (del19) lung tumors. Tumor cells undergo metabolic crisis and cell death, resulting in rapid tumor regression in vivo in mouse NSCLC xenografts. Consistently, positron emission tomography (PET) imaging with 18F-fluoro-2-deoxyglucose (18F-FDG) and 11C-glutamine (11C-Gln) of xenografts indicated reduced glucose and glutamine uptake in tumors following treatment with CB-839 + erlotinib. Therefore, PET imaging with 18F-FDG and 11C-Gln tracers can be used to non-invasively measure metabolic response to CB-839 and erlotinib combination therapy.
AuthorsMilica Momcilovic, Sean T Bailey, Jason T Lee, Michael C Fishbein, Clara Magyar, Daniel Braas, Thomas Graeber, Nicholas J Jackson, Johannes Czernin, Ethan Emberley, Matthew Gross, Julie Janes, Andy Mackinnon, Alison Pan, Mirna Rodriguez, Melissa Works, Winter Zhang, Francesco Parlati, Susan Demo, Edward Garon, Kostyantyn Krysan, Tonya C Walser, Steven M Dubinett, Saman Sadeghi, Heather R Christofk, David B Shackelford
JournalCell reports (Cell Rep) Vol. 18 Issue 3 Pg. 601-610 (01 17 2017) ISSN: 2211-1247 [Electronic] United States
PMID28099841 (Publication Type: Journal Article)
CopyrightCopyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Chemical References
  • Benzeneacetamides
  • CB-839
  • Carbon Radioisotopes
  • Radiopharmaceuticals
  • Thiadiazoles
  • Glutamine
  • Fluorodeoxyglucose F18
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • AMP-Activated Protein Kinases
  • Glutaminase
Topics
  • AMP-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)
  • Animals
  • Apoptosis (drug effects)
  • Autophagy (drug effects)
  • Benzeneacetamides (therapeutic use, toxicity)
  • Carbon Radioisotopes (chemistry)
  • Carcinoma, Non-Small-Cell Lung (diagnostic imaging, drug therapy, pathology)
  • Cell Line, Tumor
  • ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
  • Erlotinib Hydrochloride (therapeutic use, toxicity)
  • Fluorodeoxyglucose F18 (chemistry)
  • Glutaminase (antagonists & inhibitors, metabolism)
  • Glutamine (chemistry, metabolism)
  • Humans
  • Lung Neoplasms (diagnostic imaging, drug therapy, pathology)
  • Mice
  • Mice, SCID
  • Mutation
  • RNA Interference
  • Radiopharmaceuticals (chemistry)
  • Thiadiazoles (therapeutic use, toxicity)
  • Transplantation, Heterologous

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