Journal
BLOOD
Volume 122, Issue 5, Pages 738-748Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-08-447441
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Funding
- National Health and Medical Research Council of Australia
- Cancer Council of Victoria
- Cancer Council of South Australia
- Leukaemia Foundation of Australia
- Leukemia and Lymphoma Society
- Victorian Cancer Agency
- Australian Cancer Research Foundation
- Australian Research Council Federation
- Alfred Hospital Foundation
- Victorian State Government Operational Infrastructure Support
- Institut National du Cancer [PLBIO09-267]
- InNaBioSante Research Foundation
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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.
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