Selective BCL-2 Inhibition by ABT-199 Causes On Target Cell Death in Acute Myeloid Leukemia
By Rongqing Pan, L. Hogdal, J. Benito, D. Bucci, Lina Han, G. Borthakur, J. Cortes, D. DeAngelo, Lakeisha Debose, H. Mu and 22 more. Cancer Discovery, 2013
663 citations recorded by the source corpus.
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.
Subfields: Genetics, Hematology, Public Health, Environmental and Occupational Health
View Paper: https://www.semanticscholar.org/paper/01269457b1db8f1eba95c21468a41885f4a3174c
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Citations in the corpus
- Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy (2017, background): “In addition, we and others have shown that AML and other hematologic malignancies widely overexpress Bcl-2 (Coustan-Smith et al., 1996; Iqbal et al., 2006; Pan et al., 2014; Reed, 2008).”
- A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia (2016, background): “Interestingly, BCL2 was depleted in all AML cell lines except OCI-AML3, which carries a BAX pE41fs*33 mutation (Figure 3E), suggesting BAX mutations as candidate mediators of resistance to BCL2 inhibitors, a promising therapeutic strategy in AML (Chan et al., 2015; Pan et al., 2014).”