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Editorials
priming results in a lower apoptotic threshold.5-7 Thus priming of anti-apoptotic BCL2 family proteins in cancer leads to increased sensitivity to therapy, as well as mak- ing BCL2 proteins excellent targets for therapy.5-7
Venetoclax (ABT-199) is a potent and selective inhibitor of BCL2.8 The importance of BCL2 in DLBCL is well established. The t(14;18) translocation, occurring in approximately 20% of DLBCL, juxtaposes BCL2 to the immunoglobulin heavy chain gene enhancers resulting in overexpression.9 While this translocation is most fre- quently found in the germinal center B-cell subtype of DLBCL, amplification and transcriptional upregulation of BCL2 are typically found in the activated B-cell molecular subtype.10 Despite this, the clinical success of venetoclax in DLBCL has been disappointing, with an overall response rate of only 18%, regardless of BCL2 expression level.11
These findings led Smith et al. to propose a role for other anti-apoptotic proteins in DLBCL survival. To investigate this possibility, they employed venetoclax as well as A-1331852 and S63845, selective inhibitors for BCLXL and MCL1, respectively, as tools to determine the role of each anti-apoptotic protein in DLBCL survival. Using primary cells isolated from patients’ samples, as well as a panel of cell lines representing the main sub- types of DLBCL, they demonstrated that all three
inhibitors displayed activity in both the patients’ samples and the cell lines. About half of the cell lines were prefer- entially sensitive to only one inhibitor, suggesting sole dependence on that anti-apoptotic family member for survival.
However, four of the 18 cell lines and at least two of the seven patients’ samples showed sensitivity to two inhibitors, suggesting co-dependence on more than one anti-apoptotic protein for survival, a characteristic report- ed in other hematologic malignancies.12 Resistance to all three mimetics was seen in six of the 18 cell lines; how- ever, the mechanism of resistance was not explored. To further support a role for MCL1 and BCLXL in DLBCL the authors showed that silencing the anti-apoptotic pro- teins with short interfering (si)RNA was sufficient to induce apoptosis in cell lines sensitive to S63845 and A- 1331852, respectively.
Based on the sensitivity data, the authors determined the expression levels and ratios of the BCL2 proteins and found that expression was highly variable between cell lines. Concluding that expression alone could not account for sensitivity to the inhibitors they moved on to examine protein interactions. Previous studies in other hematolog- ic malignancies had demonstrated that the binding pat- tern of pro-apoptotic proteins to anti-apoptotic proteins is also a predictor of sensitivity to these small molecule
Figure 1. Schematic of the mechanism of action of selective BCL2 family inhibitors. Inhibitors disrupt interactions between anti-apoptotic BCL2 family members (green) and either the BH3-only activator protein BIM (orange) or the pro-apoptotic effectors BAX and BAK (red). This results in the release of activated effectors (solid arrows) or BIM, which can activate the effectors (dashed arrows) resulting in mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release. The inhibitors in red were the ones used in the study by Smith et al.4
haematologica | 2020; 105(8)