Profiling of pyrimidine and arginine metabolism in NSCLC identified Malate-Aspartate Shuttle as the backbone network

Abstract Metabolic shifts are crucial for cellular proliferation, however, the roles of various metabolic pathways and their interconnections in NSCLC remain unclear. This lack of understanding in metabolic shifts precludes better cancer management as well as effective therapeutic interventions. To bridge this gap, using network biology and RNA expression data complemented with wet lab experiments, metabolism in NSCLC has been studied in detailed furnishing new insights and therapeutic avenues. This study has revealed that the Malate-Aspartate Shuttle (MAS) is the backbone of nitrogen metabolic circuit, i.e., pyrimidine and arginine metabolic pathways. Several genes from the MAS (GOT1, GOT2, MDH2) are differentially regulated and are the target of therapeutic interventions, further providing the relevance of this network. Furthermore, when GOT1 was downregulated, it affected the expression of several cell cycle related genes (CCNA2, CCNB1, CCND1) and VEGF in KRAS mutated cell lines suggesting potential synthetic lethality interaction. Therefore, these experiments provide concrete evidence that MAS components, particularly GOT1, is a potential therapeutic candidate in NSCLC that could further evaluated in broader experimental conditions.