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

Thomas, Daniel, Powell, Jason A., Vergez, Francois, Segal, David H., Nguyen, Nhu-Y. N., Baker, Adele, Teh, Tse-Chieh, Barry, Emma F., Sarry, Jean-Emmanuel, Lee, Erwin M., Nero, Tracy L., Jabbour, Anissa M., Pomilio, Giovanna, Green, Benjamin D., Manenti, Stephane, Glaser, Stefan P., Parker, Michael W., Lopez, Angel F., Ekert, Paul G., Lock, Richard B., Huang, David C. S., Nilsson, Susie K., Récher, Christian, Wei, Andrew H. and Guthridge, Mark A. 2013, Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription, Blood, vol. 122, no. 5, pp. 738-748, doi: 10.1182/blood-2012-08-447441.

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Title Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription
Author(s) Thomas, Daniel
Powell, Jason A.
Vergez, Francois
Segal, David H.
Nguyen, Nhu-Y. N.
Baker, Adele
Teh, Tse-Chieh
Barry, Emma F.
Sarry, Jean-Emmanuel
Lee, Erwin M.
Nero, Tracy L.
Jabbour, Anissa M.
Pomilio, Giovanna
Green, Benjamin D.
Manenti, Stephane
Glaser, Stefan P.
Parker, Michael W.
Lopez, Angel F.
Ekert, Paul G.
Lock, Richard B.
Huang, David C. S.
Nilsson, Susie K.
Récher, Christian
Wei, Andrew H.
Guthridge, Mark A.ORCID iD for Guthridge, Mark A.
Journal name Blood
Volume number 122
Issue number 5
Start page 738
End page 748
Total pages 11
Publisher American Society of Hematology
Place of publication Washington, D.C.
Publication date 2013-08-01
ISSN 0006-4971
Summary 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.
Language eng
DOI 10.1182/blood-2012-08-447441
Indigenous content off
Field of Research 1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
1114 Paediatrics and Reproductive Medicine
HERDC Research category C1.1 Refereed article in a scholarly journal
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