Characterization of mechanisms of acquired Venetoclax-insensitivity in B-cell precursor acute lymphoblastic leukemia

The FDA approved BCL-2 inhibitor Venetoclax shows high activity in relapsed/refractory CLL and promising results in preclinical and clinical studies in ALL. Still, resistance can be acquired over time. In this study, we modeled VEN resistance in a BCP-ALL cell line and investigated underlying mechanisms in order to identify strategies to overcome VEN insensitivity. After continuous exposure to increasing concentrations of VEN over time, VEN insensitive lines displayed increasing EC50 values from 4 nM to 26.2 µM. We could not identify any mutations in the BCL2 gene. No differences in the protein expression of BCL-2 and the anti-apoptotic protein BCL-XL, but a significant up-regulation of the anti-apoptotic protein MCL-1 were observed when comparing VEN insensitive to sensitive lines. Using BH3 profiling, we could identify a clearly reduced dependence on BCL-2 and an increased dependence on MCL-1 in all VEN insensitive lines. Upon VEN exposure, the pro-apoptotic protein BIM is released from BCL-2 but sequestered by MCL-1. By co-targeting BCL-2 and MCL-1 with VEN and the MCL-1 inhibitor S63845 we could synergistically induce cell death by releasing BIM from both BCL-2 and MCL-1.

Publication History

Article published online:
13 May 2020