Unconventional Pathways of Nitrogen Metabolism in Lung Cancer

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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.By integrating metabolomics profiling with bioinformatics analysis, we discovered that cells and tumors harboring LKB1/KRAS co‐mutations share metabolomic signatures of perturbed nitrogen handling. In particular, KRAS/LKB1 co‐mutants are addicted to a urea cycle enzyme, carbamoyl phosphate synthetase 1 (CPS1). The selective dependence of KRAS/LKB1 co‐mutants on CPS1 is not due to the canonical activity of the enzyme. Instead, CPS1 stimulates an unconventional pathway of nitrogen flow from ammonia into pyrimidines. While further investigating why these cells need to recapture ammonia to initiate pyrimidine synthesis, we noted that co‐mutant human cells lines and mouse tumors up‐regulate the ‘hexosamine biosynthesis pathway (HBP)’ gene set. A focused RNAi screen and pharmacological inhibition of HBP showed that KRAS/LKB1 co‐mutants are selectively sensitive to suppression of Glutamine‐Fructose‐6‐Phosphate Transaminase 2 (GFPT2), a key enzyme in the HBP.These experiments establish the functional significance of two nitrogen‐related metabolic pathways ‐ the urea cycle and the HBP ‐ in a select population of lung cancer cells. The results suggest a model where enhanced activity of the HBP limits the availability of glutamine to serve as a direct nitrogen for conventional pyrimidine biosynthesis, forcing the cells instead to recapture ammonia via CPS1. Altogether, the work identifies a novel metabolic co‐dependence in cancer and may point towards a new therapeutic strategy in KRAS/LKB1 co‐mutant tumors.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.