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: Marco Colamonici, Gavin Blyth, Diana Saleiro, Amy Szilard, Meghan Bliss-Moreau, Francis J Giles, Jessica K Altman, Elspeth M Beauchamp, Leonidas C Platanias
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 10 Pg. 8062-70 (Apr 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25823922 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Enzyme Inhibitors
• Imidazoles
• OSI 027
• Phosphoinositide-3 Kinase Inhibitors
• Thiazoles
• Triazines
• Alpelisib
• MTOR protein, human
• Class I Phosphatidylinositol 3-Kinases
• TOR Serine-Threonine Kinases

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Class I Phosphatidylinositol 3-Kinases (antagonists & inhibitors, metabolism)
• Enzyme Inhibitors (administration & dosage, pharmacology)
• Humans
• Imidazoles (administration & dosage, pharmacology)
• Leukemia, Myeloid, Acute (drug therapy, enzymology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Signal Transduction
• TOR Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Thiazoles (administration & dosage, pharmacology)
• Triazines (administration & dosage, pharmacology)
• U937 Cells