Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Abstract

Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by excessive proliferation and accumulation of immature myeloid blasts in the bone marrow. AML has a very poor 5-year survival rate of just 16% in the UK; hence, more efficacious, tolerable, and targeted therapy is required. Persistent leukemia stem cell (LSC) populations underlie patient relapse and development of resistance to therapy. Identification of critical oncogenic signaling pathways in AML LSC may provide new avenues for novel therapeutic strategies. The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway, is often hyperactivated in AML, required to sustain the oncogenic potential of LSCs. Growing evidence suggests that targeting key components of this pathway may represent an effective treatment to kill AML LSCs. Despite this, accruing significant body of scientific knowledge, PI3K/Akt/mTOR inhibitors have not translated into clinical practice. In this article, we review the laboratory-based evidence of the critical role of PI3K/Akt/mTOR pathway in AML, and outcomes from current clinical studies using PI3K/Akt/mTOR inhibitors. Based on these results, we discuss the putative mechanisms of resistance to PI3K/Akt/mTOR inhibition, offering rationale for potential candidate combination therapies incorporating PI3K/Akt/mTOR inhibitors for precision medicine in AML.

PIM Kinases in Multiple Myeloma

“…In addition, PIM kinases are critical downstream of ABL (Abelson) and FLT3 (FMS-related tyrosine kinase 3) oncogenes and are required in driving tumorigenesis. Constitutively active FLT3 signaling up-regulates PIM1 expression and PIM is a key contributor to FLT3-induced proliferative and anti-apoptotic pathways [ 9 ]. BCR-ABL plays an important role in mediated cell transformation through induced PIM1 expression via active STAT5.…”

Mechanisms Involved in the Promoting Activity of Fibroblasts in HTLV-1-Mediated Lymphomagenesis: Insights into the Plasticity of Lymphomatous Cells

“…The discrepancy between our results and the above studies may be explained by recent findings showing how cancer cells react to a signalling blockade. In fact, this highly active pro-survival pathway is sustained by considerable positive feedback [ 39 ], as also demonstrated by the failure of PI3K/Akt inhibitors as monotherapy in most clinical trials [ 40 , 41 ]. Thus, cancer cells adapt very rapidly to PI3K inhibition, mainly due to feedback signals leading to activation or enhanced expression of growth factor receptors, such as IR/IRS1/IGF-1R, which, in turn, reactivate PI3K [ 42 , 43 ].…”

Research update on the anticancer effects of buparlisib (Review)

“…The uncontrolled activation of the PI3K/AKT/mTOR pathway, which is closely associated with several types of cancer, is involved in tumorigenesis, proliferation, invasion, cell cycle progression, apoptosis, metastasis and chemotherapy resistance (2,24,25). Recent studies have shown that the PI3K/AKT/mTOR pathway is also associated with angiogenesis, cytoskeleton, inflammatory response and oxidative stress (26)(27)(28).…”