title: 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 with18F-fluoro-2-deoxyglucose (18F-FDG) and11C-glutamine (11C-Gln) of xenografts indicated reduced glucose and glutamine uptake in tumors following treatment with CB-839 + erlotinib. Therefore, PET imaging with18F-FDG and11C-Gln tracers can be used to non-invasively measure metabolic response to CB-839 and erlotinib combination therapy.
authors.affiliation: Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Milica
authors.initials: M
authors.lastname: Momcilovic
authors.affiliation: Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Sean T
authors.initials: ST
authors.lastname: Bailey
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Clara
authors.initials: C
authors.lastname: Magyar
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Braas
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Graeber
authors.affiliation: Department of Medicine Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Jackson
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Czernin
authors.affiliation: Calithera Biosciences, South San Francisco, CA 94080, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Emberley
authors.affiliation: Calithera Biosciences, South San Francisco, CA 94080, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gross
authors.affiliation: Calithera Biosciences, South San Francisco, CA 94080, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Janes
authors.affiliation: Calithera Biosciences, South San Francisco, CA 94080, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Mackinnon
authors.affiliation: Calithera Biosciences, South San Francisco, CA 94080, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Pan
authors.affiliation: Calithera Biosciences, South San Francisco, CA 94080, USA.
authors.forename: Mirna
authors.initials: M
authors.lastname: Rodriguez
authors.affiliation: Calithera Biosciences, South San Francisco, CA 94080, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Works
authors.affiliation: Calithera Biosciences, South San Francisco, CA 94080, USA.
authors.forename: Winter
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Calithera Biosciences, South San Francisco, CA 94080, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Parlati
authors.affiliation: Calithera Biosciences, South San Francisco, CA 94080, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Demo
authors.affiliation: Department of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Garon
authors.affiliation: Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Kostyantyn
authors.initials: K
authors.lastname: Krysan
authors.affiliation: Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Tonya C
authors.initials: TC
authors.lastname: Walser
authors.affiliation: Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Saman
authors.initials: S
authors.lastname: Sadeghi
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Heather R
authors.initials: HR
authors.lastname: Christofk
authors.affiliation: Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: dshackelford@mednet.ucla.edu.
authors.forename: David B
authors.initials: DB
authors.lastname: Shackelford
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D044482:Benzeneacetamides / Q000627:therapeutic use / Q000633:toxicity*; D002250:Carbon Radioisotopes / Q000737:chemistry; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use / Q000633:toxicity*; D019788:Fluorodeoxyglucose F18 / Q000737:chemistry; D005972:Glutaminase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005973:Glutamine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D034622:RNA Interference; D019275:Radiopharmaceuticals / Q000737:chemistry; D013830:Thiadiazoles / Q000627:therapeutic use / Q000633:toxicity*; D014183:Transplantation, Heterologous
chemical_list: D044482:Benzeneacetamides; C000593334:CB-839; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D013830:Thiadiazoles; D005973:Glutamine; D019788:Fluorodeoxyglucose F18; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D055372:AMP-Activated Protein Kinases; D005972:Glutaminase
keywords: AMPK; CB-839; EGFR; PET imaging; erlotinib; glutamine; lung cancer; metabolic crisis