Blockade of Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase and Murine Double Minute Synergistically Induces Apoptosis in Acute Myeloid Leukemia via BH3-Only Proteins Puma and Bim
- 14 March 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 70 (6), 2424-2434
- https://doi.org/10.1158/0008-5472.can-09-0878
Abstract
Molecular aberrations of the Ras/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK and/or Murine double minute (MDM2)/p53 signaling pathways have been reported in 80% and 50% of primary acute myeloid leukemia (AML) samples and confer poor outcome. In this study, antileukemic effects of combined MEK inhibition by AZD6244 and nongenotoxic p53 activation by MDM2 antagonist Nutlin-3a were investigated. Simultaneous blockade of MEK and MDM2 signaling by AZD6244 and Nutlin-3a triggered synergistic proapoptotic responses in AML cell lines [combination index (CI) = 0.06 ± 0.03 and 0.43 ± 0.03 in OCI/AML3 and MOLM13 cells, respectively] and in primary AML cells (CI = 0.52 ± 0.01). Mechanistically, the combination upregulated levels of BH3-only proteins Puma and Bim, in part via transcriptional upregulation of the FOXO3a transcription factor. Suppression of Puma and Bim by short interfering RNA rescued OCI/AML3 cells from AZD/Nutlin-induced apoptosis. These results strongly indicate the therapeutic potential of combined MEK/MDM2 blockade in AML and implicate Puma and Bim as major regulators of AML cell survival. Cancer Res; 70(6); 2424–34Keywords
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