Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription

Daniel Thomas, Jason A. Powell, Francois Vergez, David H. Segal, Nhu Y.N. Nguyen, Adele Baker, Tse Chieh Teh, Emma F. Barry, Jean Emmanuel Sarry, Erwin M. Lee, Tracy L. Nero, Anissa M. Jabbour, Giovanna Pomilio, Benjamin D. Green, Stéphane Manenti, Stefan P. Glaser, Michael W. Parker, Angel F. Lopez, Paul G. Ekert, Richard B. LockDavid C.S. Huang, Susie K. Nilsson, Christian Récher, Andrew H. Wei, Mark A. Guthridge

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 familymember,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 p110a isoform of PI3K, which leads to a loss of association between Bcl-xL and Bak. The simultaneous loss ofMcl-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.

Original languageEnglish
Pages (from-to)738-748
Number of pages11
JournalBlood
Volume122
Issue number5
DOIs
Publication statusPublished - 1 Aug 2013

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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