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

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

Author(s): 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;
Details: Publication Year 2013-08-01,Volume 122,Issue #5,Page 738-748
Journal Title: BLOOD
Publication Type: Journal Article
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.
Publisher: AMER SOC HEMATOLOGY
Keywords: HEMATOPOIETIC-CELL SURVIVAL; BH3 MIMETIC ABT-737; PHOSPHOINOSITIDE 3-KINASE; BH3-ONLY PROTEINS; BCL-2 PROTEINS; IL-3 RECEPTOR; PHASE-I; APOPTOSIS; FAMILY; ACTIVATION
Research Division(s): Cancer And Haematology; Cell Signalling And Cell Death; Chemical Biology
Publisher's Version: https://doi.org/10.1182/blood-2012-08-447441

Creation Date: 2013-08-01 12:00:00