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

Author:

Thomas Daniel1,Powell Jason A.1,Vergez Francois2,Segal David H.3,Nguyen Nhu-Y. N.4,Baker Adele4,Teh Tse-Chieh4,Barry Emma F.1,Sarry Jean-Emmanuel2,Lee Erwin M.5,Nero Tracy L.6,Jabbour Anissa M.7,Pomilio Giovanna4,Green Benjamin D.4,Manenti Stéphane2,Glaser Stefan P.37,Parker Michael W.68,Lopez Angel F.9,Ekert Paul G.7,Lock Richard B.5,Huang David C. S.7,Nilsson Susie K.1011,Récher Christian212,Wei Andrew H.413,Guthridge Mark A.14

Affiliation:

1. Cell Growth and Differentiation Laboratory, Division of Human Immunology, SA Pathology, Adelaide, South Australia;

2. Institut National de la Santé et de la Recherche Médicale, Cancer Research Center of Toulouse, Toulouse, France;

3. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia;

4. Australian Centre for Blood Diseases, Division of Blood Cancers, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia;

5. Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia;

6. Biota Structural Biology Laboratory, St. Vincent’s Institute of Medical Research, Victoria, Australia;

7. Walter and Eliza Hall Institute, Parkville, Victoria, Australia;

8. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia;

9. Cytokine Receptor Laboratory, Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia;

10. CSIRO Materials Science and Engineering, Clayton, Victoria, Australia;

11. Department of Anatomy and Cell Biology, Monash University, Clayton, Victoria, Australia;

12. Universite Toulouse III Paul Sabatier, Toulouse and the Service d’Hematologie, Toulouse, France; and

13. Department of Clinical Hematology, The Alfred Hospital, Melbourne, Victoria, Australia

Abstract

Key Points Simultaneous inhibition of Cdk9 and PI3K in human AML cells liberates Bak from both Mcl-1 and Bcl-xL, inducing Bak-dependent apoptosis. Dual inhibitors of Cdk9 and PI3K, such as PIK-75, have broad activity against malignant cells including human AML cells.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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