Exploring the role of cellular metabolism in anticancer drug resistance:: a metabolomics approach

Abstract

Metabolic alterations are an important aspect of cancer and also play a role in anticancer drug resistance. As drug-resistant cells can become reliant on their altered metabolism, a better understanding of this metabolic rewiring in drug-resistant cells could aid in finding novel strategies to improve current therapies. The work in this thesis describes how metabolic alterations are involved in resistance towards several anticancer agents, such as the proteasome inhibitor bortezomib. Bortezomib is widely used in the treatment of multiple myeloma, but therapy is often hampered by the occurrence of resistance. By combining mass spectrometry based metabolomics in combination with a metabolism-oriented targeted proteomics, this work provides novel mechanistic insights into the role of metabolism in mediating bortezomib resistance. For example, bortezomib-resistant cells divert glycolytic metabolites to biosynthetic pathways, resulting in high activity of the serine synthesis pathway. In addition, resistant cells show extensive rewiring of their mitochondrial energy metabolism. Interfering with these metabolic processes, such as dietary restriction or chemical inhibition of enzymatic reactions, could be novel strategies to overcome bortezomib resistance. In addition, this thesis shows that metabolism also influences the efficacy of non-cancer related drugs, in particular proteasome activators. This aspect not only shows the potential of metabolomics in screening for new drug targets, but also underscores that it is imperative to be aware of the influence of metabolism on the effect of the drug. In conclusion, the work described in this thesis illustrates that metabolism plays an important role in the effectiveness of anticancer drugs. A combination of metabolomics with other -omics techniques results in a multidimensional picture of cellular responses to drugs. The metabolic vulnerabilities described in this thesis may be exploited to improve the efficacy of specific anticancer drugs, which warrants further preclinical and clinical investigation.