Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia

Abstract

An accumulating understanding of the complex pathogenesis of acute myeloid leukemia (AML) continues to lead to promising therapeutic approaches. Among the key aberrant intracellular signaling pathways involved in AML, the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) axis is of major interest. This axis modulates a wide array of critical cellular functions, including proliferation, metabolism, and survival. Pharmacologic inhibitors of components of this pathway have been developed over the past decade, but none has an established role in the treatment of AML. This review will discuss the preclinical data and clinical results driving ongoing attempts to exploit the PI3K/AKT/mTOR pathway in patients with AML and address issues related to negative feedback loops that account for leukemic cell survival. Targeting the PI3K/AKT/mTOR pathway is of high interest for the treatment of AML, but combination therapies with other targeted agents may be needed to block negative feedback loops in leukemia cells.

Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo

“…1,2 The selective targeting of these pathways could improve the outcome of the currently available, generally unsatisfactory, treatments for patients with AML. [3][4][5] The mitogen-activated protein kinase (MAPK) pathways regulate multiple cellular processes including leukemic cell proliferation, differentiation, and apoptosis. 1,6 Two key effectors of MAPK pathways are the MAPK interacting protein kinases 1 and 2 (Mnk1/2), which are activated downstream of MAP kinases and regulate the activation of eukaryotic translation initiation factor 4E (eIF4E).…”

Distinct Dasatinib-Induced Mechanisms of Apoptotic Response and Exosome Release in Imatinib-Resistant Human Chronic Myeloid Leukemia Cells

“…Generally, autophagy pathway is negatively regulated by mTOR signaling [ 18 ]. Rapamycin inhibits mTOR pathway by directly binding to mTORC1 complex [ 32 ]. Our data demonstrated that the increased autophagy activity is mTOR-independent in imatinib-resistant CML cells ( Figure 2 E and Figure 3 B–D).…”

The mTOR inhibitor everolimus in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia: a phase Ib/II study

“…mTORC1 targeting by rapalogs could lead to unintended feedback amplification of the PI3K/AKT/mTOR pathway in AML, potentially subverting the clinical effect of targeting mTORC1 alone [ 4 , 5 ]. Several studies have demonstrated improved anti-leukemic effects in AML by targeting both mTORC1 and mTORC2 simultaneously using active site or catalytic inhibitors [ 34 ]. Interestingly, mTORC2 may be inhibited by high doses of rapamycin, leading to inactivation of AKT and ERK [ 6 ].…”