File(s) under permanent embargo
Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription
journal contributionposted on 2013-08-01, 00:00 authored by 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 Lock, David C S Huang, Susie K Nilsson, Christian Récher, Andrew H Wei, Mark GuthridgeMark Guthridge
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.