Venetoclax causes metabolic reprogramming independent of BCL-2 inhibition

• DOI: 10.1038/s41419-020-02867-2
• Publication Date: 2020-08-13T18:05:06Z
• Authors: Alba Roca-Portoles; Giovanny Rodrigue...; David Sumpton; Catherine Cloix; Margaret Mullin; Gillian M. Mackay; Katelyn O’Neill; Leandro Lemgruber; Xu Luo; Stephen W. G. Tait
• Keywords: Venetoclax

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