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|Title:||Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription|
|Citation:||Blood, 2013; 122(5):738-748|
|Publisher:||American Society of Hematology|
|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|
|Appears in Collections:||Medicine publications|
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