Dependence of venetoclax response on BAX and development of venetoclax resistance through BAX mutations. (A) Venetoclax, by engaging BCL2 as an alternative ligand, releases proapoptotic BH3-only proteins from BCL2, which then activates apoptosis effector proteins such as BAX. BAX is found predominantly in the cytosol with its COOH-terminal transmembrane region (TMR) sequestered within its hydrophobic pocket. Once activated, BAX releases its TMR to be inserted into the OMM, where BAX oligomerizes to permeabilize the OMM and induce release of cytochrome c. (B) Acquired frameshift/nonsense mutations in BAX reduce its protein expression while inactivating missense mutations in BAX such as P168A compromises its effector functions by preventing BAX TMR release and insertion into the OMM. mRNA, messenger RNA.