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

• Published in: Cell reports (Cambridge) Vol. 18; no. 3; pp. 601 - 610
• Main Authors: Momcilovic, Milica, Bailey, Sean T., Lee, Jason T., Fishbein, Michael C., Magyar, Clara, Braas, Daniel, Graeber, Thomas, Jackson, Nicholas J., Czernin, Johannes, Emberley, Ethan, Gross, Matthew, Janes, Julie, Mackinnon, Andy, Pan, Alison, Rodriguez, Mirna, Works, Melissa, Zhang, Winter, Parlati, Francesco, Demo, Susan, Garon, Edward, Krysan, Kostyantyn, Walser, Tonya C., Dubinett, Steven M., Sadeghi, Saman, Christofk, Heather R., Shackelford, David B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.01.2017; Elsevier
• Subjects: AMP-Activated Protein Kinases - antagonists & inhibitors; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; AMPK; 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; CB-839; Cell Line, Tumor; EGFR; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - metabolism; erlotinib; Erlotinib Hydrochloride - therapeutic use; Erlotinib Hydrochloride - toxicity; Fluorodeoxyglucose F18 - chemistry; Glutaminase - antagonists & inhibitors; Glutaminase - metabolism; glutamine; Glutamine - chemistry; Glutamine - metabolism; Humans; lung cancer; Lung Neoplasms - diagnostic imaging; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; metabolic crisis; Mice; Mice, SCID; Mutation; PET imaging; Radiopharmaceuticals - chemistry; RNA Interference; Thiadiazoles - therapeutic use; Thiadiazoles - toxicity; Transplantation, Heterologous; lung cancer; metabolic crisis; PET imaging; erlotinib; AMPK; glutamine; CB-839; EGFR
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.12.061

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. [Display omitted] •Targeted EGFR and GLS inhibition cooperate in vivo to induce rapid tumor regression•Measured metabolic response to EGFR and GLS inhibitors using 18F-FDG and 11C-Gln PET•EGFR and GLS inhibition induce severe energetic stress and cell death in lung tumors Momcilovic et al. report that combined inhibition of EGFR and glutaminase cooperate to drive energetic stress and activate the AMPK pathway in EGFR mutant lung tumors. Tumor cells undergo metabolic crisis and cell death, resulting in rapid tumor regression in a mouse xenograft model of lung cancer.