Cell Reports (Jan 2017)
Targeted Inhibition of EGFR and Glutaminase Induces Metabolic Crisis in EGFR Mutant Lung Cancer
- Milica 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
Affiliations
- Milica Momcilovic
- Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Sean T. Bailey
- Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Jason T. Lee
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Michael C. Fishbein
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Clara Magyar
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Daniel Braas
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Thomas Graeber
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Nicholas J. Jackson
- Department of Medicine Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Johannes Czernin
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Ethan Emberley
- Calithera Biosciences, South San Francisco, CA 94080, USA
- Matthew Gross
- Calithera Biosciences, South San Francisco, CA 94080, USA
- Julie Janes
- Calithera Biosciences, South San Francisco, CA 94080, USA
- Andy Mackinnon
- Calithera Biosciences, South San Francisco, CA 94080, USA
- Alison Pan
- Calithera Biosciences, South San Francisco, CA 94080, USA
- Mirna Rodriguez
- Calithera Biosciences, South San Francisco, CA 94080, USA
- Melissa Works
- Calithera Biosciences, South San Francisco, CA 94080, USA
- Winter Zhang
- Calithera Biosciences, South San Francisco, CA 94080, USA
- Francesco Parlati
- Calithera Biosciences, South San Francisco, CA 94080, USA
- Susan Demo
- Calithera Biosciences, South San Francisco, CA 94080, USA
- Edward Garon
- Department of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Kostyantyn Krysan
- Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Tonya C. Walser
- Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Steven M. Dubinett
- Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Saman Sadeghi
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Heather R. Christofk
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- David B. Shackelford
- Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- DOI
- https://doi.org/10.1016/j.celrep.2016.12.061
- Journal volume & issue
-
Vol. 18,
no. 3
pp. 601 – 610
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
