Fig. 6: Schematic showing navitoclax plus AZD8055 combination mechanism in MPM.

Malignant pleural mesothelioma cells are relatively “unprimed” at baseline (untreated). No one anti-apoptotic dependency is observed, but a combination of BCL-xL and MCL-1 (BIM bound to both anti-apoptotic’s). No MOMP (mitochondrial outer membrane permeabilization) occurs. When cells are treated with navitoclax, this antagonizes BCL-xL. Increased BIM protein levels are observed along with increased binding of BIM to MCL-1. Cells become more MCL-1 dependent. MCL-1 neutralizes the increased BIM pro-apoptotic signal and no MOMP occurs. When cells are treated with AZD8055, levels of MCL-1 are decreased, and BIM levels increase. BIM is neutralized/bound to both BCL-xL and MCL-1 and no MOMP occurs. When cells are treated with both navitoclax and AZD8055 in combination, BCL-xL is antagonized by navitoclax, MCL-1 levels are decreased by AZD8055 and BIM levels are increased resulting in less BIM bound to BCL-xL, more BIM bound to MCL-1 and remaining BIM activates effectors BAK/BAX, resulting in MOMP. Created with BioRender.com.