Abstract PR10: Alterations in carbon and nitrogen metabolism in lung cancer

Abstract

Abstract Lung cancer is the leading cause of cancer death worldwide. The critical barrier in lung cancer treatment is a lack of effective therapies at later stages of the disease. Lung cancer genome sequencing supports the idea that combinations of mutations act in concert to foster malignancy and disease progression. Among these, KRAS and LKB1 mutations represent “driver” changes in tumor development. Importantly, mutations in these genes also perturb signal transduction to promote a form of metabolism conducive to tumor growth. Metabolic reprogramming is considered to be fundamental to malignant transformation; thus, identifying molecular links between these mutations and metabolism, and targeting the resulting metabolic pathways, may produce better therapies. To gain broader insight into metabolic reprogramming and potential dependencies in different KRAS/LKB1 co-mutant (KL) model systems, we analyzed metabolome and gene expression profiling of tumors derived from genetically engineered mouse models of lung cancer. These two datasets independently revealed that both mouse and human KL co-mutants are associated with elevated hexosamine biosynthesis pathway (HBP) expression, a metabolic pathway that requires the interplay between nitrogen and carbon metabolism. Upregulation of the HBP in co-mutants resulted in enhanced global N-acetyl glucosamine modification (O-GlcNAcylation) and glycosylation, modification involved in important processes occurring in cancer, such as cell signaling and communication, cell-matrix interactions, immune modulation and metastasis formation. KL cells have elevated HBP metabolites and higher hexosamine biosynthesis rates. By small scale RNAi screening and chemical inhibition of the HBP, we uncovered that KL co-mutants are dependent on Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2), a rate-limiting enzyme in the pathway. GFPT2 inhibition selectively reduced KL cell growth in culture and xenografts. Importantly, high GFPT2 expression predicts poor prognosis in human NSCLC patients, considerably more so than low LKB1 expression alone. Our study illuminates the functional significance of the interplay between carbon and nitrogen metabolism in cancer, not only for primary cancer growth but also for tumor aggressiveness and may lead to new avenues for developing novel targeted therapeutics. Citation Format: Jiyeon Kim. Alterations in carbon and nitrogen metabolism in lung cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PR10.