1. Venetoclax acts through on-target BCL2 inhibition.
Venetoclax acts through on-target BCL2 inhibition. Twelve samples were analyzed (>50% viability on thaw; >5% AML blasts). A, mitochondrial BCL2 dependence correlated with release caused by BAD-HRK. Background BCL-XL dependence was removed by subtraction of HRK for a specific measure of mitochondrial BCL2 dependence. B, mitochondrial response to venetoclax was weakly related to days on venetoclax therapy. C and D, AML blast dependence on the antiapoptotic protein BCL-XL (using the HRK peptide) or the antiapoptotic protein MCL1 (using the MS1 peptide) negatively correlated with days on venetoclax. E, an index combining AML blast dependence on the antiapoptotic protein BCL-XL and the antiapoptotic protein MCL1 negatively correlated with days on venetoclax therapy. F, ROC analysis of dependence on MCL1 or BCL-XL, by arithmetically adding response to HRK peptide to that of MS1 peptide, was a perfect binary predictor of staying on venetoclax therapy more than 30 days (AUC of the ROC = 1.0). Correlations (r) and P values based on one-tailed Spearman rank-order correlation tests.
Marina Konopleva et al. Cancer Discov 2016;6:
©2016 by American Association for Cancer Research