The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors

Abstract

BCR-ABL1-specific tyrosine kinase inhibitors prolong the life of patients with chronic myeloid leukemia (CML) but cannot completely eradicate CML progenitors. The BH3 mimetic, ABT-263, targets prosurvival BCL2 family members, and has activity against CML progenitors. However, the inhibitory effect of ABT-263 on BCL-XL, which mediates platelet survival, produces dose-limiting thrombocytopenia. A second-generation BH3 mimetic, ABT-199, has been developed to specifically bind BCL2 but not BCL-XL. We determined the activity of ABT-199 against CML cell lines, as well as primary CML and normal cord blood (NCB) progenitors. We find that BCL2 expression levels predict sensitivity to ABT-199 in CML and NCB progenitors, and that high NCB BCL2 levels may explain the reported hematologic toxicities in ABT-199-treated patients. Also, while single agent ABT-199 has modest activity against CML progenitors, when combined with imatinib, ABT-199 significantly enhances imatinib activity against CML progenitors at concentrations predicted to avoid hematologic toxicities.

Phosphorylation of Bcl-2 plays an important role in glycochenodeoxycholate-induced survival and chemoresistance in HCC

“…ABT-737, which is an anticancer drug, is a Bcl-2 Homology 3 (BH-3)-mimetic that induces apoptosis by inhibiting pro-survival Bcl-2 proteins (45) and enhance the effects of epirubicin on HepG2 cells by activating autophagy and inducing apoptosis (46). A BH3 mimetic, ABT-199, has been developed to selectively bind Bcl-2 and enhances imatinib-induced cell death in chronic myeloid leukemia progenitors (47). BDA-366, a small-molecule Bcl-2-BH4 domain antagonist, can bind BH4 of Bcl-2 with high affinity and selectivity, and this Bcl-2-BH4 antagonist may provide a strategy to improve lung cancer outcome (48).…”

Inhibitor of Apoptosis Proteins (IAPs) are commonly dysregulated in GIST and can be pharmacologically targeted to enhance the pro-apoptotic activity of imatinib

“…Improving the apoptotic treatment response to imatinib represents a key goal for future therapeutic concepts in GIST. In the CML context, BCL2 inhibitors have been shown to enhance imatinib-induced cell death [25]. Quiescence and autophagy have been demonstrated as potential escape mechanisms to imatinib inhibition in GIST.…”

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

“…Venetoclax has shown synergistic effects against CML progenitor cells when combined with the tyrosine kinase inhibitor (TKI) imatinib and high expression levels of BCL-2 in CML and normal cord blood progenitors were found to predict sensitivity to venetoclax (122). More recently, Carter, Andreeff and colleagues demonstrated that TKIs can downregulate MCL-1, leading to synergy with venetoclax in killing CML cells, including quiescent cells and blast crisis cells – populations notoriously difficult to eradicate with TKIs alone (123).…”