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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.
Highlights
Acute myeloid leukemia (AML) is a highly fatal disease, as many patients do not respond to therapy or eventually relapse [1,2,3]
Using different AML cell lines (U937, MM6 and Kasumi-1), we analyzed the effects of these agents on the phosphorylation of AKT on serine 473 (Ser473), a marker of mTOR complex 2 (mTORC2) activity, and the phosphorylation of S6 ribosomal protein and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), markers of mTOR complex 1 (mTORC1) activity
We have previously shown that dual targeting of mTORC1 and mTORC2 with OSI-027 results in more potent antileukemic effects than treatment with rapamycin alone [17]
Summary
Acute myeloid leukemia (AML) is a highly fatal disease, as many patients do not respond to therapy or eventually relapse [1,2,3]. Activation of mTORC1 (a complex composed of mTOR, Raptor, PRAS40, mLST8 and DEPTOR) plays a central role in regulating initiation of mRNA translation and autophagy through its downstream targets 4E-BP1, S6K and ULK1 [9,10,11]. A new generation of catalytic mTOR inhibitors has been developed to target both mTOR complexes [12, 13, 16]. These mTOR inhibitors act by binding to the ATPbinding site of mTOR and block the activities of both mTORC1 and mTORC2 [12, 13, 16]. We have previously reported that dual targeting of mTORC1 and mTORC2 with OSI-027 results in enhanced antileukemic responses as compared to treatment with the classic mTORC1 inhibitor, rapamycin [17]
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