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

• DOI: 10.1016/j.celrep.2016.12.061
• Publication Date: 2017-01-17T19:47:24Z
• Authors: 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
• Keywords: Glutaminase; EGFR Inhibitors; Erlotinib Hydrochloride; Glutaminolysis

Cancer cells exhibit increased use of nutrients, including glucose and glutamine, to support the bioenergetic biosynthetic demands proliferation. We tested small-molecule inhibitor glutaminase CB-839 in combination with erlotinib on epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) as a therapeutic strategy simultaneously impair glutamine utilization thereby suppress tumor growth. Here, we show that cooperates drive energetic stress activate AMP-activated protein kinase (AMPK) pathway EGFR (del19) tumors. Tumor undergo metabolic crisis death, resulting rapid regression vivo mouse NSCLC xenografts. Consistently, positron emission tomography (PET) imaging 18F-fluoro-2-deoxyglucose (18F-FDG) 11C-glutamine (11C-Gln) xenografts indicated reduced uptake tumors following treatment + erlotinib. Therefore, PET 18F-FDG 11C-Gln tracers can be used non-invasively measure response therapy.