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Variable patient responses to drugs are a key issue for medicine and for drug discovery and development. Personalized medicine, that is the selection of medicines for subgroups of patients so as to maximize drug efficacy and minimize toxicity, is a key goal of twenty-first century healthcare. Currently, most personalized medicine paradigms rely on clinical judgment based on the patient's history, and on the analysis of the patients' genome to predict drug effects i.e., pharmacogenomics. However, variability in patient responses to drugs is dependent upon many environmental factors to which human genomics is essentially blind. A new paradigm for predicting drug responses based on individual pre-dose metabolite profiles has emerged in the past decade: pharmacometabonomics, which is defined as “the prediction of the outcome (for example, efficacy or toxicity) of a drug or xenobiotic intervention in an individual based on a mathematical model of pre-intervention metabolite signatures.” The new pharmacometabonomics paradigm is complementary to pharmacogenomics but has the advantage of being sensitive to environmental as well as genomic factors. This review will chart the discovery and development of pharmacometabonomics, and provide examples of its current utility and possible future developments.

Introduction KRAS was one of the earliest human oncogenes to be described and is one of the most commonly mutated genes in different human cancers, including colorectal cancer. Despite KRAS mutants being known driver mutations, KRAS has proved difficult to target therapeutically, necessitating a comprehensive understanding of the molecular mechanisms underlying KRAS-driven cellular transformation. Objectives To investigate the metabolic signatures associated with single copy mutant KRAS in isogenic human colorectal cancer cells and to determine what metabolic pathways are affected. Methods Using NMR-based metabonomics, we compared wildtype (WT)-KRAS and mutant KRAS effects on cancer cell metabolism using metabolic profiling of the parental KRASG13D/+ HCT116 cell line and its isogenic, derivative cell lines KRAS+/– and KRASG13D/–. Results Mutation in the KRAS oncogene leads to a general metabolic remodelling to sustain growth and counter stress, including alterations in the metabolism of amino acids and enhanced glutathione biosynthesis. Additionally, we show that KRASG13D/+ and KRASG13D/− cells have a distinct metabolic profile characterized by dysregulation of TCA cycle, up-regulation of glycolysis and glutathione metabolism pathway as well as increased glutamine uptake and acetate utilization. Conclusions Our study showed the effect of a single point mutation in one KRAS allele and KRAS allele loss in an isogenic genetic background, hence avoiding confounding genetic factors. Metabolic differences among different KRAS mutations might play a role in their different responses to anticancer treatments and hence could be exploited as novel metabolic vulnerabilities to develop more effective therapies against oncogenic KRAS. Graphical abstract