Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL- and mutant FLT3-expressing cells

Blood
Ellen WeisbergJames D Griffin

Abstract

Mediators of PI3K/AKT signaling have been implicated in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Studies have shown that inhibitors of PI3K/AKT signaling, such as wortmannin and LY294002, are able to inhibit CML and AML cell proliferation and synergize with targeted tyrosine kinase inhibitors. We investigated the ability of BAG956, a dual PI3K/PDK-1 inhibitor, to be used in combination with inhibitors of BCR-ABL and mutant FLT3, as well as with the mTOR inhibitor, rapamycin, and the rapamycin derivative, RAD001. BAG956 was shown to block AKT phosphorylation induced by BCR-ABL-, and induce apoptosis of BCR-ABL-expressing cell lines and patient bone marrow cells at concentrations that also inhibit PI3K signaling. Enhancement of the inhibitory effects of the tyrosine kinase inhibitors, imatinib and nilotinib, by BAG956 was demonstrated against BCR-ABL expressing cells both in vitro and in vivo. We have also shown that BAG956 is effective against mutant FLT3-expressing cell lines and AML patient bone marrow cells. Enhancement of the inhibitory effects of the tyrosine kinase inhibitor, PKC412, by BAG956 was demonstrated against mutant FLT3-expressing cells. Finally, BAG956 and rapamycin/RAD001 were shown to c...Continue Reading

References

Dec 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·G Q Daley, D Baltimore
Nov 1, 1996·Leukemia & Lymphoma·B Calabretta, T Skorski
Dec 3, 1999·British Journal of Haematology·F RavandiH M Kantarjian
Feb 5, 2000·Biochimica Et Biophysica Acta·F Vazquez, W R Sellers
Dec 21, 2000·Current Oncology Reports·A JakubowiakS D Nimer
Sep 13, 2001·Biochimica Et Biophysica Acta·E BuchdungerB J Druker
Apr 30, 2002·International Journal of Cancer. Journal International Du Cancer·Ben K Seon
Jul 10, 2003·Blood Cells, Molecules & Diseases·Kiyotaka KawauchiShin ichiro Ohkawa
Sep 3, 2003·Nature Reviews. Cancer·Derek L Stirewalt, Jerald P Radich
Oct 16, 2003·Biochemical and Biophysical Research Communications·Ning GaoXianglin Shi
Feb 21, 2004·Proceedings of the National Academy of Sciences of the United States of America·M Golam MohiBenjamin G Neel
May 6, 2004·Annals of Hematology·T HaferlachC Schoch
May 19, 2004·Biochemical and Biophysical Research Communications·Maria JönssonJan-Ingvar Jönsson
Aug 26, 2004·British Journal of Haematology·Pier Luigi TazzariAlberto M Martelli
Oct 27, 2004·Apoptosis : an International Journal on Programmed Cell Death·M OsakiH Ito
Nov 20, 2004·Blood·Christian RécherBernard Payrastre
Feb 16, 2005·Cancer Cell·Ellen WeisbergJames D Griffin
Mar 31, 2005·Journal of the American Chemical Society·Laura A BanaszynskiThomas J Wandless

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Citations

May 7, 2011·Targeted Oncology·Shin Ogita, Patricia Lorusso
Dec 2, 2010·The Journal of Biological Chemistry·Kumiko NagashimaJannik N Andersen
Dec 17, 2008·Hematology·Catriona H Jamieson
Dec 3, 2009·Haematologica·Sophie ParkDidier Bouscary
Apr 1, 2009·Future Medicinal Chemistry·Sauveur-Michel MairaFrédéric Stauffer
Feb 9, 2011·Leukemia & Lymphoma·Amanda J RedigLeonidas C Platanias
Feb 10, 2010·Expert Opinion on Investigational Drugs·Munira Shabbir, Robert Stuart
Jul 1, 2009·Expert Opinion on Medical Diagnostics·Hilmar M Warenius
Aug 15, 2009·Expert Opinion on Investigational Drugs·Alberto M MartelliJames A McCubrey
Feb 12, 2013·Experimental Hematology·Tomasz StoklosaPawel Wlodarski
Mar 13, 2010·Cancer Treatment Reviews·Jean Pierre Bourquin, Shai Izraeli
Feb 27, 2010·Critical Reviews in Oncology/hematology·Axel SchulenburgPeter Valent
Jun 15, 2014·Pharmacology & Therapeutics·Nadine Houédé, Philippe Pourquier
May 27, 2009·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Ellen WeisbergJames D Griffin
Jul 26, 2008·Cancer Letters·Gisella VolpeDaniela Cilloni
Mar 16, 2011·The Journal of Pharmacy and Pharmacology·Sazal PatyarBikash Medhi
Jun 10, 2015·Leukemia Research·Domenico SalemiAlessandra Santoro
Jun 25, 2015·Assay and Drug Development Technologies·Douglas S AuldJonathon P Orme
Oct 23, 2016·Clinical Lymphoma, Myeloma & Leukemia·Mona HassaneinRiad El Fakih
Jan 11, 2018·Cells·Riad El FakihMona Hassanein
Feb 19, 2019·Expert Opinion on Investigational Drugs·Joseph Cioccio, David Claxton
Jul 14, 2010·Oncogene·E WeisbergJ D Griffin

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