Title: Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription
Authors: Thomas, D
Powell, JA
Vergez, F
Segal, DH
Nguyen, NYN
Baker, A
Teh, TC
Barry, EF
Sarry, JE
Lee, EM
Nero, TL
Jabbour, AM
Pomilio, G
Green, BD
Manenti, S
Glaser, SP
Parker, MW
Lopez, AF
Ekert, PG
Lock, RB
Huang, DCS
Nilsson, SK
Recher, C
Wei, AH
Guthridge, MA
Issue Year: 2013
Publisher AMER SOC HEMATOLOGY
Series BLOOD: 122(5): 738-748
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 p110 alpha isoform of PI3K, which leads to a loss of association between Bcl-x(L) and Bak. The simultaneous loss of Mcl-1 and Bcl-x(L) 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.
URI: https://publications.svi.edu.au/publications/1667
Other Identifiers 10.1182/blood-2012-08-447441
Publication type Article
Grant ID GNT1021645
Find it online http://www.bloodjournal.org/content/bloodjournal/122/5/738.full.pdf