@article{203b0e2891e84619bd8b0d0a6b785794,
title = "Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription",
abstract = "Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 familymember,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 p110a isoform of PI3K, which leads to a loss of association between Bcl-xL and Bak. The simultaneous loss ofMcl-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.",
author = "Daniel Thomas and Powell, {Jason A.} and Francois Vergez and Segal, {David H.} and Nguyen, {Nhu Y.N.} and Adele Baker and Teh, {Tse Chieh} and Barry, {Emma F.} and Sarry, {Jean Emmanuel} and Lee, {Erwin M.} and Nero, {Tracy L.} and Jabbour, {Anissa M.} and Giovanna Pomilio and Green, {Benjamin D.} and St{\'e}phane Manenti and Glaser, {Stefan P.} and Parker, {Michael W.} and Lopez, {Angel F.} and Ekert, {Paul G.} and Lock, {Richard B.} and Huang, {David C.S.} and Nilsson, {Susie K.} and Christian R{\'e}cher and Wei, {Andrew H.} and Guthridge, {Mark A.}",
note = "Funding Information: These studies were supported by funding from the National Health and Medical Research Council of Australia, Cancer Councils of Victoria and 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, the Institut National du Cancer (PLBIO09-267), the InNaBioSant{\'e}Research Foundation (RESISTAML program), and infrastructure support was provided by the Victorian Government Operational Infrastructure Support Scheme to St. Vincent{\textquoteright}s Institute. The authors thank Yang-Yen (National Taiwan University Medical School), Shaun Jackson (Australian Centre for Blood Diseases), Peter Shepherd (University of Auckland), Lorraine O{\textquoteright}Reilley (Walter and Eliza Hall Institute), and Andrew Wilks (SYN|thesis) for reagents. The authors thank Tiffany Khong, Nathalie Gallay, Camille Fialin, Anuratha Srikumar, Daniel Gray, Andrea Reitsma, Dani Cardozo, and Estelle Saland for expert technical assistance. The authors thank Dr C{\'e}cile Demur (Collection des H{\'e}mopathies Malignes de l{\textquoteright}INSERM Midi-Pyr{\'e}n{\'e}es) and Dr Andrew Spencer for patient samples and reagents. The authors thank Wallace Langdon (University of Western Australia) for critical reading of the manuscript. Funding Information: These studies were supported by funding from the National Health and Medical Research Council of Australia, Cancer Councils of Victoria and 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, the Institut National du Cancer (PLBIO09-267), the InNaBioSant? Research Foundation (RESISTAML program), and infrastructure support was provided by the Victorian Government Operational Infrastructure Support Scheme to St. Vincent's Institute.",
year = "2013",
month = aug,
day = "1",
doi = "10.1182/blood-2012-08-447441",
language = "English",
volume = "122",
pages = "738--748",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "5",
}