Abstract
Defective apoptosis mediated by BAK or BAX underlies various human pathologies including autoimmune and degenerative conditions. The mitochondrial channel protein VDAC2 interacts with BAK and BAX through a common interface to either inhibit BAK or to facilitate BAX apoptotic activity. Using a newly developed small molecule (WEHI-3773) that inhibits the interaction between VDAC2 and BAK or BAX, we reveal contrasting effects on BAX and BAK apoptotic activity. WEHI-3773 inhibits apoptosis mediated by BAX by blocking VDAC2-mediated BAX recruitment to mitochondria. Conversely, WEHI-3773 primes BAK for apoptosis by impairing its inhibitory sequestration by VDAC2 on the mitochondrial membrane. In cells expressing both BAX and BAK, repressing their association with VDAC2 promotes apoptosis, because once BAK is activated, it further activates BAX through a feed-forward mechanism. In some leukemias, mutation or loss of BAX is a key driver of resistance to the BH3-mimetic anti-cancer drug venetoclax. Strikingly, promoting BAK-mediated killing by small molecule dissociation of the VDAC2 interaction can overcome this resistance in different leukemia models. These data reveal a hitherto unappreciated level of coordination of BAX and BAK apoptotic activity through their interaction with VDAC2 that may be targeted therapeutically.
Competing Interest Statement
GD, PEC, RB, DCSH, MvD, GL, YQY, DMM, FS, YK, AG, AWR, RWB, PEC, KLo and AHW are employees of the Walter and Eliza Hall Institute of Medical Research that receives milestone payments related to sales of venetoclax. AHW provides medical advice and receives honoraria and research funding to the institution from AbbVie.
