Venetoclax causes metabolic reprogramming independent of BCL-2 inhibition

Abstract

BH3-mimetics are a new class of anti-cancer drugs that inhibit anti-apoptotic Bcl-2 proteins. In doing so, BH3-mimetics sensitise to cell death. Venetoclax is a potent, BCL-2 selective BH3-mimetic that is clinically approved for use in chronic lymphocytic leukaemia. Venetoclax has also been shown to inhibit mitochondrial metabolism, this is consistent with a proposed role for BCL-2 in metabolic regulation. We used venetoclax to understand BCL-2 metabolic function. Similar to others, we found that venetoclax inhibited mitochondrial respiration. In addition, we also found that venetoclax impairs TCA cycle activity leading to activation of reductive carboxylation. Importantly, the metabolic effects of venetoclax were independent of cell death because they were also observed in apoptosis-resistant BAX/BAK-deficient cells. However, unlike venetoclax treatment, inhibiting BCL-2 expression had no effect on mitochondrial respiration. Unexpectedly, we found that venetoclax also inhibited mitochondrial respiration and the TCA cycle in BCL-2 deficient cells and in cells lacking all anti-apoptotic BCL-2 family members. Investigating the basis of this off-target effect, we found that venetoclax-induced metabolic reprogramming was dependent upon the integrated stress response and ATF4 transcription factor. These data demonstrate that venetoclax affects cellular metabolism independent of BCL-2 inhibition. This off-target metabolic effect has potential to modulate venetoclax cytotoxicity.

Intrinsic OXPHOS limitations underlie cellular bioenergetics in leukemia

“…The preponderance of evidence related to mitochondrial bioenergetics in AML indicates that active repression of OXPHOS is advantageous to the leukemia phenotype. Related to this, although several reports have linked AML chemoresistance to apparent increases in ‘OXPHOS reliance’ ( Farge et al, 2017 ; Guièze et al, 2019 ; Liu et al, 2020 ; Roca-Portoles et al, 2020 ), such conclusions are based largely on intact cellular respirometry in which OXPHOS kinetics are not directly quantified. To address the specific role for OXPHOS in AML chemoresistance, we conducted a series of experiments in chemosensitive HL-60 cells and compared the results to HL-60 cells made to be refractory to venetoclax ( Figure 8A–B ).…”

Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma

“…Thus, tigecycline and other mitochondrial inhibitors could be useful in metabolically reprogrammed malignancies. For instance, the Bcl-2 inhibitor venetoclax has been shown to inhibit mitochondrial respiration [ 41 ], although it appears to have higher cytotoxicity in myeloma plasma cells with reduced mitochondrial respiration. The increased OXPHOS in MM would be a drawback for venetoclax treatment, but the addition of tigecycline to a venetoclax regimen could be a therapeutic opportunity in MM or other B-cell malignancies, especially with a MYC contribution [ 42 ].…”

Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?

“…Targeted therapies such as the BH3-mimetic Venetoclax, designed to selectively inhibit the anti-apoptotic protein BCL-2, inhibits mitochondrial respiration and disrupts TCA cycle flux by causing mitochondrial deformity, initiation of the integrated stress response and activation of ATF4, possibly potentiating the pro-apoptotic mechanism of action and enhancing cell death [167]. Intriguingly, ATF4 has also been linked to the induction of both necrosis and apoptosis following either glucose deprivation or 2-Deoxyglucose treatment, respectively [168], demonstrating a potential mechanism through which impaired glucose acquisition kills.…”

“…The development of BH3 mimetics such as the BCL-2 selective inhibitor Venetoclax has proven a success and is now approved for clinical management of a range of haematological malignancies, however other targeted BH3 mimetics have failed to succeed in this regard [174]. The mixed fortunes of translating BH3 mimetic in vitro to clinical efficacy is in part due to toxicity towards normal cells [174], but may also be due to the often-overlooked metabolic implications of therapeutically disrupting mitochondrial function [30,167]. Firstly, induction of partial-MOMP has the potential to further transform malignant cells rather than eliminate them [31] and secondly, treatment with some BH3 mimetics has been reported to increase intracellular ROS levels [175], which can be further transformative to the cell if at sub-toxic concentrations.…”