Abstract B07: Characterization of branched-chain aminotransferase 1 as a novel therapeutic target for small cell lung cancer

Few studies have explored tumor metabolism to target small cell lung cancer (SCLC), for which treatment options are limited and eventually fail with resistance. The objective of this study is to identify novel biomarkers and therapeutic targets among molecular changes specific to the cancer cells relative to precancerous precursor cells. In our previous study, comparative profiling of precancerous cells with SCLC cells revealed branched-chain aminotransferase1 (Bcat1) as one of the most upregulated genes in the cancer cells relative to their precursors as well as normal lung. Based on this result, we hypothesize that the elevated Bcat1 plays a role in promoting SCLC. Here, we confirmed elevated Bcat1 protein expression in mouse SCLC cells relative to precancerous cells and in human SCLC lines. Targeting Bcat1 in mouse and human SCLC cells with shRNA or small-molecule inhibitors significantly reduced colony expansion in soft agar and formation of subcutaneous tumors in athymic nude mice. Inhibition of Bcat1 also reduced protein synthesis rate as measured by puromycin incorporation into protein. Additionally, we found Bcat1 plays a significant role in leucine catabolism in mouse SCLC using a coupled enzymatic assay. Taken together, these novel findings suggest that elevated Bcat1 promotes SCLC growth by supporting protein synthesis, which is necessary for proliferating cells. Given the proven safety profile of existing inhibitors of Bcat1, our findings are significant in supporting the concept of targeting Bcat1 as a novel and particularly valuable therapeutic strategy for SCLC. Citation Format: Napoleon B. Butler, Keebeom Kim, Dong-wook Kim, Kwon Park. Characterization of branched-chain aminotransferase 1 as a novel therapeutic target for small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B07.