Rational combination of dual PI3K/mTOR blockade and Bcl-2/-xL inhibition in AML

Abstract

Acute myeloid leukemia (AML) continues to represent an area of critical unmet need with respect to new and effective targeted therapies. The Bcl-2 family of pro- and antiapoptotic proteins stands at the crossroads of cellular survival and death, and the expression of and interactions between these proteins determine tumor cell fate. Malignant cells, which are often primed for apoptosis, are particularly vulnerable to the simultaneous disruption of cooperative survival signaling pathways. Indeed, the single agent activity of agents such as mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase kinase (MEK) inhibitors in AML has been modest. Much work in recent years has focused on strategies to enhance the therapeutic potential of the bona fide BH3-mimetic, ABT-737, which inhibits B-cell lymphoma 2 (Bcl-2) and Bcl-xL. Most of these strategies target Mcl-1, an antiapoptotic protein not inhibited by ABT-737. The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways are central to the growth, proliferation, and survival of AML cells, and there is much interest currently in pharmacologically interrupting these pathways. Dual inhibitors of PI3K and mTOR overcome some intrinsic disadvantages of rapamycin and its derivatives, which selectively inhibit mTOR. In this review, we discuss why combining dual PI3K/mTOR blockade with inhibition of Bcl-2 and Bcl-xL, by virtue of allowing coordinate inhibition of three mutually synergistic pathways in AML cells, may be a particularly attractive therapeutic strategy in AML, the success of which may be predicted for by basal Akt activation.

Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia

“…For example, sorafenib sensitized AML cells to ABT-737 73 and obatoclax 74 as does targeting phosphoinositide 3-kinase and mTOR in combination with BH3 mimetics. 75 As we demonstrated that MCL1 overexpression rescued cell death induced by SPHK1 targeted therapies, and combinational therapies with ABT-737 and agents targeting the SPHK1/S1PR2 axis induced synergistic lethality in AML, these rational combinational therapies may prove efficacious for the treatment of AML. Targeting these 2 cooperative survival signaling pathways may have the capacity to overcome the diverse molecular landscapes associated with heterogeneous diseases such as AML.…”

Identification of Aberrantly Methylated and Silenced Genes in Acute Myeloid Leukemia by Combined Methylation/expression Analysis

“…Constitutive NF-kappaB signaling is discovered in 40% of AML patients, which promotes cell proliferation and resists apoptosis (57,58), thus contributing to leukemogenesis (59). PI3K-Akt signaling pathway was activated frequently in AML (60), and corresponding target drug is a promising therapy (61). In addition to these pathways mainly involving cell proliferation/apoptosis, the PD1-expression and PD-1 checkpoint pathway was also implicated to be activated in SYNJ2 hypermethylated group.…”

Des-gamma-carboxy prothrombin antagonizes the effects of Sorafenib on human hepatocellular carcinoma through activation of the Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways

“…Further analysis indicated that DCP intimately links to the apoptotic pathway through activation of many kinase cascades. The PI3K/Akt/mTOR and MEK/ERK signaling pathways extensively phosphorylate apoptotic effector molecules ( e.g ., Bcl-2, Mcl-1, Bad, Bim, caspase-9 and many others) [32, 33]. Akt upregulates Bcl-2 and Mcl-1 expression via the cyclic adenosine monophosphate response element binding protein (CREB).…”

“…Numerous reports have shown that the effects of the PI3K/Akt/mTOR signaling pathway on apoptosis are mediated by the Akt phosphorylation of key apoptotic effector molecules, namely Bcl-2, Mcl-1, Bax, and caspase-9 [32, 33]. Activation of the PI3K/Akt kinases leads to antiapoptosis, whereas inhibition of the PI3K/Akt/mTOR signaling pathway induces apoptosis of cancer cells [34, 35].…”