Fig. 1

Potential mechanisms of venetoclax resistance. Ventoclax recognizes the BH3-biding groove of BCL2 and eases BAK/BAX complex formation, releasing cytochrome c from mitochondria and promote tumor cell apoptosis. Mutation of BCL2 changes protein conformation and impedes venetoclax binding to its target thus against its pro-apoptic effect. Also, genetic alterations such as mutation of TP53 and amplification of 1q23 combined with running out of ATP on mitochondria membrane lead AMPK/PKA pathway aberrantly activating, diminishing the permeability of mitochondria membrane and inducing venetoclax resistance. Interact with non-tumor cells in surrounding microenvironment though membrane molecules activate multiple signaling pathways including NF-κB and PI3K/AKT, which upregulating the anti-apoptic proteins and relseasing varity of inflammatory cytokines. Gene mutation and immune phenotype alteration promote clonal evolution, dysregulate cancer signaling pathways activation and proteins expression, finally lead to venetoclax resistance