Research Papers:
Dual targeting of acute myeloid leukemia progenitors by catalytic mTOR inhibition and blockade of the p110α subunit of PI3 kinase
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Abstract
Marco Colamonici1,2, Gavin Blyth1,2, Diana Saleiro1,2, Amy Szilard1,2, Meghan Bliss-Moreau1, Francis J. Giles1,2, Jessica K. Altman1,2,3, Elspeth M. Beauchamp1,2,3 and Leonidas C. Platanias1,2,3
1 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
2 Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
3 Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA
Correspondence to:
Leonidas C. Platanias, email:
Keywords: AML, mTOR signaling, PI3 kinase
Received: January 01, 2015 Accepted: February 03, 2015 Published: March 10, 2015
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.
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PII: 3509