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.
