Rational combination of dual PI3K/mTOR blockade and Bcl-2/-xL inhibition in AML.
Acute myeloid leukemia (AML) continues to represent an area of critical unmet need with respect to new and effective targeted therapies. The Bcl-2 family of pro- and antiapoptotic proteins stands at the crossroads of cellular survival and death, and the expression of and interactions between these proteins determine tumor cell fate. Malignant cells, which are often primed for apoptosis, are particularly vulnerable to the simultaneous disruption of cooperative survival signaling pathways. Indeed, the single agent activity of agents such as mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase kinase (MEK) inhibitors in AML has been modest. Much work in recent years has focused on strategies to enhance the therapeutic potential of the bona fide BH3-mimetic, ABT-737, which inhibits B-cell lymphoma 2 (Bcl-2) and Bcl-xL. Most of these strategies target Mcl-1, an antiapoptotic protein not inhibited by ABT-737. The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways are central to the growth, proliferation, and survival of AML cells, and there is much interest currently in pharmacologically interrupting these pathways. Dual inhibitors of PI3K and mTOR overcome some intrinsic disadvantages of rapamycin and its derivatives, which selectively inhibit mTOR. In this review, we discuss why combining dual PI3K/mTOR blockade with inhibition of Bcl-2 and Bcl-xL, by virtue of allowing coordinate inhibition of three mutually synergistic pathways in AML cells, may be a particularly attractive therapeutic strategy in AML, the success of which may be predicted for by basal Akt activation.
Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia;
Pankit
P
Vachhani
Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia; Virginia Commonwealth University Massey Cancer Center, Richmond, Virginia.
Prithviraj
P
Bose
Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia; Virginia Commonwealth University Massey Cancer Center, Richmond, Virginia.
Mohamed
M
Rahmani
Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia; Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia; Institute of Molecular Medicine, Virginia Commonwealth University; and Virginia Commonwealth University Massey Cancer Center, Richmond, Virginia stgrant@vcu.edu.
Steven
S
Grant
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D009596:Nitrophenols / Q000008:administration & dosage*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction; D020123:Sirolimus / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000502:physiology
C501332:ABT-737; C494811:BCL2L1 protein, human; D001713:Biphenyl Compounds; D009596:Nitrophenols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
AML; Bcl-2; Bcl-xL; PI3K; mTOR