SRA

The metabolic dependencies of cancer cells have significant potential to be exploited to improve the diagnosis and treatment of cancer. Creatine riboside (CR) is a novel urinary metabolite associated with risk and prognosis in lung and liver cancer. However, the source of high creatine riboside levels in cancer patients, as well as its implications for the treatment of these aggressive cancers remain unclear. By integrating RNA sequencing and whole exome sequencing of non-small cell lung cancer tissues we sought to understand the source of creatine riboside and the tumor biology associated with this novel metabolite. Utilising multiple lung and liver cancer cohorts, next generation sequencing data was combined with global metabolomics analysis of human tumors, and matched liquid biopsies together with functional studies to reveal that dysregulation of the mitochondrial urea cycle and nucleotide imbalance are associated with high creatine riboside levels and are indicators of poor prognosis. Creatine riboside-high cancer cells were auxotrophic for arginine, revealing a metabolic vulnerability that may be exploited therapeutically. This highlights the potential of creatine riboside not only as a poor prognosis biomarker but also as a companion biomarker to inform the administration of arginine-targeted therapies in precision medicine strategies to improve cancer patient survival. Overall design: non-small cell lung cancer tissues were analysed by RNA sequencing.