Selective BCL-2 Inhibition by ABT-199 Causes On-Target Cell Death in Acute Myeloid Leukemia

Abstract

B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC50 was approximately 10 nM, and cell death occurred within 2 h. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia (CLL), a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profiling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT-199 in AML.

Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition

“…Accordingly, we hypothesized that mitochondrial priming might potentiate the antileukemic effects that result from GLS1 inhibition. We cocultured AML cells with increasing doses of the BH3 mimetic ABT-199, which specifically inhibits BCL-2, 28 along with CB-839. In OCI-AML2 and MOLM-14 cells, ABT-199 and CB-839 synergized to induce Annexin V staining ( Figure 5C-D).…”

MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors

“…Two of these agents, the specific Bcl-2 inhibitor ABT-199 21 and the Bcl-2/Bcl-x L /Bcl-w inhibitor ABT-263 (navitoclax), 22 have shown activity in preclinical studies in AML. 21,23 Previous studies, however, have reported that Mcl-1, which is frequently upregulated at the time of AML relapse, 24 confers resistance to BH3 mimetics.…”

“…Two of these agents, the specific Bcl-2 inhibitor ABT-199 21 and the Bcl-2/Bcl-x L /Bcl-w inhibitor ABT-263 (navitoclax), 22 have shown activity in preclinical studies in AML. 21,23 Previous studies, however, have reported that Mcl-1, which is frequently upregulated at the time of AML relapse, 24 confers resistance to BH3 mimetics. [25][26][27][28] Thus, the ability of NAE inhibition to upregulate Noxa not only provides new insight into the cytotoxic action of MLN4924 in AML, but also gives impetus for further study of MLN4924/BH3 mimetic combinations.…”

“…21,23 Additional studies have shown that Mcl-1 overexpression, which frequently occurs in AML at relapse, 24 is a mechanism of resistance to ABT-737. [25][26][27] The ability of MLN4924 to upregulate Noxa and neutralize Mcl-1 (Figure 2d) raised the possibility that MLN4924 might sensitize AML cells to agents such as ABT-199 and ABT-263 (an orally bioavailable analog of ABT-737), which was indeed observed ( Figure 5).…”

Acute myeloid leukemia—Major progress over four decades and glimpses into the future

“…This presented the rationale for investigating venetoclax in AML. Preclinical studies confirmed its activity in AML cell lines, in murine primary xenografts, and in patient AML samples [155]. A phase 1 single agent study of venetoclax in AML investigated escalating doses (20-800 mg daily) in 32 patients with refractory-relapsed AML.…”