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https://hdl.handle.net/2440/85687
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Type: | Journal article |
Title: | Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription |
Author: | Thomas, D. Powell, J. Vergez, F. Segal, D. Nguyen, N. Baker, A. Teh, T. Barry, E. Sarry, J. Lee, E. Nero, T. Jabbour, A. Giovanna, P. Green, B. Manenti, S. Glaser, S. Parker, M. Lopez, A. Ekert, P. Lock, R. et al. |
Citation: | Blood, 2013; 122(5):738-748 |
Publisher: | American Society of Hematology |
Issue Date: | 2013 |
ISSN: | 0006-4971 1528-0020 |
Statement of Responsibility: | Daniel Thomas, Jason A. Powell ... Angel F. Lopez ... Mark A. Guthridge |
Abstract: | Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). A screen for compounds that downregulate Mcl-1 identified the kinase inhibitor, PIK-75, which demonstrates marked proapoptotic activity against a panel of cytogenetically diverse primary human AML patient samples. We show that PIK-75 transiently blocks Cdk7/9, leading to transcriptional suppression of MCL-1, rapid loss of Mcl-1 protein, and alleviation of its inhibition of proapoptotic Bak. PIK-75 also targets the p110α isoform of PI3K, which leads to a loss of association between Bcl-xL and Bak. The simultaneous loss of Mcl-1 and Bcl-xL association with Bak leads to rapid apoptosis of AML cells. Concordantly, low Bak expression in AML confers resistance to PIK-75–mediated killing. On the other hand, the induction of apoptosis by PIK-75 did not require the expression of the BH3 proteins Bim, Bid, Bad, Noxa, or Puma. PIK-75 significantly reduced leukemia burden and increased the survival of mice engrafted with human AML without inducing overt toxicity. Future efforts to cotarget PI3K and Cdk9 with drugs such as PIK-75 in AML are warranted. |
Keywords: | Cells, Cultured HL-60 Cells Animals Mice, Inbred NOD Mice, Knockout Humans Mice Mice, SCID Sulfonamides Hydrazones Proto-Oncogene Proteins c-bcl-2 Antineoplastic Agents Protein Kinase Inhibitors Xenograft Model Antitumor Assays Signal Transduction Transcription, Genetic Gene Expression Regulation, Leukemic Cyclin-Dependent Kinase 9 Leukemia, Myeloid, Acute HEK293 Cells Molecular Targeted Therapy Myeloid Cell Leukemia Sequence 1 Protein Phosphoinositide-3 Kinase Inhibitors |
Rights: | © 2013 by The American Society of Hematology |
DOI: | 10.1182/blood-2012-08-447441 |
Published version: | http://dx.doi.org/10.1182/blood-2012-08-447441 |
Appears in Collections: | Aurora harvest 7 Medicine publications |
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