title: Dual targeting of acute myeloid leukemia progenitors by catalytic mTOR inhibition and blockade of the p110α subunit of PI3 kinase.
abstract: The mammalian target of rapamycin (mTOR) and phosphoinositide-3-kinase (PI3K) pathways are often aberrantly activated in acute myeloid leukemia (AML) and play critical roles in proliferation and survival of leukemia cells. We provide evidence that simultaneous targeting of mTOR complexes with the catalytic mTOR inhibitor OSI-027 and of the p110α subunit of PI3K with the specific inhibitor BYL-719 results in efficient suppression of effector pathways and enhanced induction of apoptosis of leukemia cells. Importantly, such a combined targeting approach results in enhanced suppression of primitive leukemic progenitors from patients with AML. Taken together, these findings raise the possibility of combination treatments of mTOR and p110α inhibitors as a unique approach to enhance responses in refractory AML.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Colamonici
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Gavin
authors.initials: G
authors.lastname: Blyth
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Saleiro
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Szilard
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Bliss-Moreau
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Altman
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA.
authors.forename: Elspeth M
authors.initials: EM
authors.lastname: Beauchamp
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA.
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; D013844:Thiazoles; D014227:Triazines; C568605:OSI 027; C585539:Alpelisib; C546842:MTOR protein, human
keywords: AML; PI3 kinase; mTOR signaling
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