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

Cell Rep. 2017 Jan 17;18(3):601-610. doi: 10.1016/j.celrep.2016.12.061.

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.

Keywords: AMPK; CB-839; EGFR; PET imaging; erlotinib; glutamine; lung cancer; metabolic crisis.

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors
  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Apoptosis / drug effects*
  • Autophagy / drug effects
  • Benzeneacetamides / therapeutic use
  • Benzeneacetamides / toxicity*
  • Carbon Radioisotopes / chemistry
  • Carcinoma, Non-Small-Cell Lung / diagnostic imaging
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride / therapeutic use
  • Erlotinib Hydrochloride / toxicity*
  • Fluorodeoxyglucose F18 / chemistry
  • Glutaminase / antagonists & inhibitors*
  • Glutaminase / metabolism
  • Glutamine / chemistry
  • Glutamine / metabolism
  • Humans
  • Lung Neoplasms / diagnostic imaging
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology
  • Mice
  • Mice, SCID
  • Mutation
  • RNA Interference
  • Radiopharmaceuticals / chemistry
  • Thiadiazoles / therapeutic use
  • Thiadiazoles / toxicity*
  • Transplantation, Heterologous

Substances

  • Benzeneacetamides
  • CB-839
  • Carbon Radioisotopes
  • Radiopharmaceuticals
  • Thiadiazoles
  • Glutamine
  • Fluorodeoxyglucose F18
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • AMP-Activated Protein Kinases
  • Glutaminase