Abstract 4710: Evaluation of the glutaminase inhibitor CB-839 in non-small cell lung cancer

Glutamine is an abundant nutrient used by cancer cells to support energetic and biosynthetic pathways. Given that many cancer cells exhibit glutamine dependence, there has been interest in developing inhibitors targeting glutaminase, which catalyzes conversion of glutamine to glutamate. CB-839 is a glutaminase inhibitor with preclinical efficacy in suppressing cancer cell growth in culture and in vivo. It is now in Phase I clinical trials for solid and hematological malignancies, including non-small cell lung cancer (NSCLC). Here we set out to identify biomarkers predicting sensitivity of NSCLC cells to CB-839, using a highly annotated panel of 81 cell lines. These lines had heterogeneous oncogenotypes and displayed about a 5-fold range in their ability to tolerate glutamine deprivation. Assessing CB-839 sensitivity in ∼40 lines revealed a 5-fold difference in growth suppression among cell lines. There was a strong correlation between CB-839 sensitivity and both glutamine dependence and glutamate secretion. In a subset of 4 representative cell lines, CB-839 suppressed [U-13C]glutamine metabolism in both sensitive and insensitive cells suggesting other mechanisms contribute to CB-839 sensitivity. To identify potential biomarkers predicting CB-839 sensitivity, the glutamine dependence and drug sensitivity phenotypes were correlated with several orthogonal high-content data sets including mutational analysis of commonly-mutated oncogenes and tumor suppressors; sensitivity to chemotherapeutic agents; gene expression arrays; and reverse phase protein arrays (RPPA). Although we did not identify a strong correlation between mutational status and CB-839 sensitivity, expression of phospho-Rb (S807/811) and Smad3 did correlate with drug sensitivity. In addition, sensitivity to glutamine withdrawal correlated with expression of c-Myc and MEK2 protein. While further work is necessary to examine the importance of these proteins in glutamine metabolism, we hypothesize that one or more of these may represent novel biomarkers predicting sensitivity to glutaminase inhibition. Citation Format: Lindsey K. Boroughs, Pei-Hsuan Chen, Ling Cai, Mirna Rodriguez, Winter Zhang, Kenneth E. Huffman, Lauren A. Byers, Luc Girard, Adi F. Gazdar, John V. Heymach, Michael A. White, John D. Minna, Ethan Emberley, Alison Pan, Frank Parlati, Ralph J. DeBerardinis. Evaluation of the glutaminase inhibitor CB-839 in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4710. doi:10.1158/1538-7445.AM2015-4710