Mechanisms of resistance to venetoclax. The intrinsic apoptotic pathway can be engaged by stimuli that regulate BCL-2 and MCL1 interactions with BH3-only proteins (ie, PUMA and NOXA), modulating the activation of the effector proteins BAX and BAK. Once activated, BAX and BAK cause MOMP, leading to the release of proapoptotic proteins. Cytochrome C leads to apoptosome formation that recruits and activates caspase. Mechanisms of resistance to venetoclax described in the papers by Thijssen et al and Thomalla et al are shown in the blue box. MOMP, mitochondrial outer membrane permeabilization; SMAC, second mitochondria-derived activator of caspase.