Figure 5.

Model for metabolic rewiring associated to ibrutinib resistance in CLL lymphocytes. Upon ibrutinib treatment, ibrutinib resistant cells initiate a compensation mechanism increasing fatty acid oxidation metabolism as well as α-KG production from glutamate, to maintain mitochondrial homeostasis. In line with this, we propose that α-KG follows preferentially an oxidation process in the TCA. Transporters are colored in purple, enzymes in green, and inhibitors in red. Enzymes overexpressed in CLL lymphocytes are in bold green characters. Blue arrows indicate reactions increased in basal ibrutinib resistant cells compared to the sensitive subset. Purple arrows represent the processes that are increased in resistant cells upon ibrutinib treatment. Dashed red arrows represent the processes inhibited upon ibrutinib treatment. Brown arrows indicate the proposed alternative metabolic rewiring to increase fatty acid and Acetyl-CoA availability.