Figure 3.

Mechanisms of acquired resistance to venetoclax in CLL. Although the factors contributing to disease progression on venetoclax are still the subject of ongoing research, available studies have identified a diverse range of mechanisms, which broadly target three cellular processes: apoptosis, metabolism, and the cell cycle. The most common recurrent mechanism of venetoclax resistance identified in CLL to date is the acquisition of the BCL2 G101V mutation, although other BCL2 mutations have also been detected (e.g., D103Y, D103E, D103V, V156D, R107_R110dup, A113G, R129L). Other mechanisms include the upregulation of alternative pro-survival proteins, particularly MCL1 and BCLxL, amplification of a positive regulatory subunit of AMPK called PRKAB2, leading to increased oxidative phosphorylation, homozygous deletions of CDKN2A/B, and BTG1 mutations.