Journal article

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

Daniel Thomas, Jason A Powell, Francois Vergez, David H Segal, Nhu-Y N Nguyen, Adele Baker, Tse-Chieh Teh, Emma F Barry, Jean-Emmanuel Sarry, Erwin M Lee, Tracy L Nero, Anissa M Jabbour, Giovanna Pomilio, Benjamin D Green, Stephane Manenti, Stefan P Glaser, Michael W Parker, Angel F Lopez, Paul G Ekert, Richard B Lock Show all

BLOOD | AMER SOC HEMATOLOGY | Published : 2013

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 p110α isoform of PI3K, which leads t..

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Grants

Awarded by Institut National du Cancer


Funding Acknowledgements

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 InNaBioSante Research Foundation (RESISTAML program), and infrastructure support was provided by the Victorian Government Operational Infrastructure Support Scheme to St. Vincent'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'Reilley (Walter and Eliza Hall Institute), and Andrew Wilks (SYN vertical bar 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 Cecile Demur (Collection des Hemopathies Malignes de l'INSERM Midi-Pyrenees) and Dr Andrew Spencer for patient samples and reagents. The authors thank Wallace Langdon (University of Western Australia) for critical reading of the manuscript.