Abstract 1830: Targeted inhibition of EGFR and glutaminase induces metabolic crisis in EGFR mutant lung cancer

Cancer cells exhibit increased use of nutrients including glucose and glutamine to support the bioenergetic and biosynthetic demands of proliferation. We tested CB-839, a small molecule inhibitor of glutaminase that impairs glutamine utilization, in combination with erlotinib on 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 synergizes with erlotinib to drive energetic stress and activate the 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 CB-839 + erlotinib treatment. Therefore, PET imaging with 18F-FDG and 11C-Gln can be used to non-invasively monitor tumor metabolic and therapeutic response to CB-839 and erlotinib combination therapy. Note: This abstract was not presented at the meeting. Citation Format: Milica Momcilovic, Sean T. Bailey, Jason T. Lee, Daniel Braas, Thomas G. Graeber, Melissa Works, Francesco Parlati, Susan Demo, Tonya C. Walser, Steven M. Dubinett, Saman Sadeghi, Heather Christofk, David B. Shackelford. Targeted inhibition of EGFR and glutaminase induces metabolic crisis in EGFR mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1830. doi:10.1158/1538-7445.AM2017-1830