Metabolic plasticity and adaptive resistance to metabolic inhibitors in tumor cells

Although tumor metabolism is becoming a major source of inspiration to develop new anticancer drugs, the current number of breakthrough discoveries under clinical evaluation is so far limited. One explanation besides the usual PK and PD issues that stop drug candidates during their development is the metabolic plasticity of tumors. There are indeed numerous examples where tumors were shown to adapt their metabolic preferences according to the (un-)availability of nutrients or the (in-)capacity to transform them into biosynthetic intermediates and ATP. Direct consequences of metabolic adaptation are the development of resistance and the progressive loss of activity of the drug. Such metabolic adaptations can occur through the selection of cancer cell clones bearing a mutation that supports the alternate metabolic route. However, the intricate network of biochemical pathways that govern cell metabolism can also offer mutation-independent modes of adaptation for cells to fulfill their bioenergetic needs through another path than the one blocked by the administered drug. Our study aims to identify the optimal combination of two drugs targeting metabolic pathways in order to prevent a possible escape for cancer cells. To do so, we used 3-bromopyruvate (3-BrPA) as a first metabolism-targeting drug to induce metabolic addictions to given pathways that could be targeted in a second time (synthetic lethality). Our data indicate that a pre-challenge with 3-BrPA leads to metabolic alterations within tumor cells, leading in particular to a strict dependence towards MCT4 expression to support glycolytic flux and cell growth. This metabolic adaptation can be therapeutically targeted. More generally, our study highlights a new strategy to overcome metabolic plasticity and associated therapy resistance by treating tumor cells with two metabolic inhibitors, in a sequential mode, with a synthetic lethality purpose