Abstract

Targeting Resistance to Proteasome Inhibitor Therapy: A Metabolomics Approach

Celia Berkers, Assistant Professor, Utrecht University

Most diseases as well as the action of therapeutic agents result in metabolic changes. Therefore, studying these metabolic changes can aid in identifying new targets for therapeutic intervention. Proteasome inhibition has emerged as an important strategy for the treatment of cancer. However, treatment with proteasome inhibitors is often hampered by the occurrence of both primary and acquired resistance. This resistance may be associated with changes in the metabolism of tumour cells. Interestingly, cells may become reliant on such drug-induced metabolic reprogramming, a vulnerability that may be exploited for therapy. In this study, the metabolic pathways involved in resistance to the proteasome inhibitor bortezomib were elucidated using a mass spectrometry-based metabolomics approach. To this end, bortezomib-sensitive and -resistant cell lines were profiled using a combination of steady-state metabolomics experiments and stable isotope labelling approaches. Our studies revealed that the metabolic profiles of bortezomib-sensitive and resistant cells differed significantly. Importantly, bortezomib-resistant cells have become dependent on the uptake of specific nutrients from their environment due to their rewired metabolism. In conclusion, our data indicate a therapeutic opportunity for nutrient starvation in the treatment of bortezomib-resistant tumours.