Metabolic plasticity and adaptive resistance to metabolic inhibitors in tumor cells

Abstract

Nowadays, tumor metabolism represents an attractive field to develop new anticancer drugs. Cancer cells may however adapt their metabolic preferences to counteract a specific pathway inhibition. Our study aims to identify the optimal combination of metabolism-targeting drugs, in order to prevent a possible escape for cancer cells. The rationale behind our work is, with a first drug, to force cancer cells to become addicted to specific bioenergetic fuels/pathways in order to render a second drug lethal. For the proof of principle, we used 3-bromopyruvate (3-BrPA) as a first metabolism-targeting drug and generated clones resistant to this compound. We showed in three different 3-BrPA-resistant (3-BrPA-R) cell lines that resistance was associated with the downregulation of MCT1, a lactate/H+ membrane co-transporter. Using Seahorse respirometry and metabolite quantification, we confirmed that the induced lack of MCT1 was associated with a deficit of 3-BrPA-R cancer cells to take up extracellular lactate and use it as a fuel. Furthermore, we found that a pre-challenge with 3-BrPA led to the selection of cancer cells with a strict dependence towards MCT4 expression to support glycolytic flux and cell growth. This shift in MCT expression was further associated with an increased resistance of 3-BrPA-R cells to hypoxia and a preferred location of resistant clones within the hypoxic core of 3D tumor spheroids. Our work positions MCT4 inhibitors as attractive drug candidates to be combined with 3BrPA. This hypothesis is currently being tested and if validated, will shed light on how to overcome metabolic plasticity and associated therapy resistance