Figure 1.

Main pathways for targeting venetoclax resistance. New therapeutic agents can inhibit other antiapoptotic proteins such as MCL-1 or increase the expression of proapoptotic BH-3 only proteins (NOXA, PUMA), in order to release cytochrome c, leading to apoptotic cell death. Targeting mitochondrial metabolism (i.e., OxPhos) or mitochondrial machinery (electronic transport chain, mitochondrial DNA replication, mitochondrial translation, mitochondrial structure, etc.) may increase the efficacy of BH-3 mimetics, by inducing the mitochondrial integrative stress response driven by the transcription factor ATF4. Abbreviation: TCA, tricarboxylic acid cycle. Cyt c: cytochrome c.