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

被引:596
作者
Pan, Rongqing [1 ]
Hogdal, Leah J. [4 ,5 ]
Benito, Juliana M. [1 ]
Bucci, Donna [6 ]
Han, Lina [1 ]
Borthakur, Gautam [1 ]
Cortes, Jorge [1 ]
DeAngelo, Daniel J. [5 ]
Debose, LaKeisha [1 ]
Mu, Hong [1 ]
Doehner, Hartmut [9 ]
Gaidzik, Verena I. [9 ]
Galinsky, Ilene [5 ]
Golfman, Leonard S. [2 ]
Haferlach, Torsten [10 ]
Harutyunyan, Karine G. [1 ]
Hu, Jianhua [3 ]
Leverson, Joel D. [7 ]
Marcucci, Guido [6 ]
Mueschen, Markus [8 ]
Newman, Rachel [3 ]
Park, Eugene [8 ]
Ruvolo, Peter P. [1 ]
Ruvolo, Vivian [1 ]
Ryan, Jeremy [5 ]
Schindela, Sonja [10 ]
Zweidler-McKay, Patrick [2 ]
Stone, Richard M. [5 ]
Kantarjian, Hagop [1 ]
Andreeff, Michael [1 ]
Konopleva, Marina [1 ]
Letai, Anthony G. [4 ,5 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Pediat, Houston, TX 77030 USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA
[4] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA
[5] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[6] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA
[7] AbbVie Inc, N Chicago, IL USA
[8] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA
[9] Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany
[10] MLL Munich Leukemia Lab, Munich, Germany
关键词
CHRONIC LYMPHOCYTIC-LEUKEMIA; ANTI-APOPTOTIC MCL-1; ABT-737; SENSITIVITY; BAX; MITOCHONDRIA; RESISTANCE; ABT-263; POTENT; PUMA;
D O I
10.1158/2159-8290.CD-13-0609
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. SIGNIFICANCE: Although targeting BCL-2 has largely been investigated in lymphoid cancers, we present preclinical results of targeting BCL-2 in AML. These results support clinical testing of the small-molecule BCL-2 antagonist ABT-199 in AML, accompanied by testing of predictive biomarkers used in this study.
引用
收藏
页码:362 / 375
页数:14
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