Cancer Discov 2014 Mar 17;4(3):362-75. Epub 2013 Dec 17.
Departments of 1Leukemia, 2Pediatrics, and 3Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas; 4Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; 5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; 6The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; 7AbbVie Inc., North Chicago, Illinois; and 8Department of Laboratory Medicine, University of California San Francisco, San Francisco, California; 9Department of Internal Medicine III, University Hospital of Ulm, Ulm; 10MLL Munich Leukemia Laboratory, Munich, Germany.
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 nmol/L, and cell death occurred within 2 hours. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, 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.