Colamonici Marco, Blyth Gavin, Saleiro Diana, Szilard Amy, Bliss-Moreau Meghan, Giles Francis J, Altman Jessica K, Beauchamp Elspeth M, Platanias Leonidas C
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.
Oncotarget. 2015 Apr 10;6(10):8062-70. doi: 10.18632/oncotarget.3509.
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.
雷帕霉素哺乳动物靶点（mTOR）和磷酸肌醇-3-激酶（PI3K）通路在急性髓系白血病（AML）中常被异常激活，并在白血病细胞的增殖和存活中起关键作用。我们提供的证据表明，用催化性mTOR抑制剂OSI-027同时靶向mTOR复合物，并用特异性抑制剂BYL-719靶向PI3K的p110α亚基，可有效抑制效应通路并增强白血病细胞凋亡的诱导。重要的是，这种联合靶向方法可增强对AML患者原始白血病祖细胞的抑制作用。综上所述，这些发现增加了联合使用mTOR和p110α抑制剂进行治疗的可能性，这是一种增强难治性AML反应的独特方法。
