The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients

Martelli, Alberto M.; Evangelisti, Camilla; Chiarini, Francesca; McCubrey, James A.

doi:10.18632/oncotarget.114

Cited by 228 publications

(206 citation statements)

References 153 publications

(180 reference statements)

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“…Other potential downstream PI3K targets that may contribute to BEZ235/panobinostat interactions include PDK1, which promotes cell survival in an AKT-dependent as well as an AKT-independent manner [40]. In addition, one of the mechanisms by which AKT increases cell survival is by phosphorylating the serine/threonine protein kinase GSK3 at serine 9/21, an event that leads to its cytoplasmic sequestration and inhibition [41]. The observations that GSK3 was dephosphorylated in cells treated with BEZ235/panobinostat along with down-regulation of the GSK3 downstream target β-Catenin and c-Myc proteins level indicate GSK3 inactivation.…”

Section: Discussionmentioning

confidence: 99%

PI3K/mTOR Inhibition Markedly Potentiates HDAC Inhibitor Activity in NHL Cells through BIM- and MCL-1–Dependent Mechanisms In Vitro and In Vivo

Rahmani

Aust

Benson

et al. 2014

Clinical Cancer Research

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Purpose To explore the efficacy and define mechanisms of action of co-administration of the PI3K/mTOR inhibitor BEZ235 and pan-HDAC inhibitor panobinostat in DLBCL cells. Experimental Design Various DLBCL cells were exposed to panobinostat and BEZ235 alone or together after which apoptosis and signaling/survival pathway perturbations were monitored by flow cytometry and Western blot analysis. Genetic strategies defined the functional significance of such changes, and xenograft mouse models were used to assess tumor growth and animal survival. Results Panobinostat and BEZ235 interacted synergistically in ABC-, GC-, and double-hit DLBCL cells, and MCL cells, but not normal CD34+ cells. Synergism was associated with pronounced AKT dephosphorylation, GSK3 dephosphorylation/activation, Mcl-1 downregulation, Bim up-regulation and increased Bcl-2/Bcl-xL binding, diminished Bax/Bak binding to Bcl-2/Bcl-xL/Mcl-1, increased γH2A.X phosphorylation and histone H3/H4 acetylation, and abrogation of p21CIP1 induction. BEZ235/panobinostat lethality was not susceptible to stromal/microenvironmental forms of resistance. Genetic strategies confirmed significant functional roles for AKT inactivation, Mcl-1 down-regulation, Bim up-regulation, and Bax/Bak in synergism. Finally, co-administration of BEZ235 with panobinostat in immunocompromised mice bearing SU-DHL4-derived tumors significantly reduced tumor growth in association with similar signaling changes observed in vitro, and increased animal survival compared to single agents. Conclusions BEZ235/panobinostat exhibits potent anti-DLBCL activity, including in poor-prognosis ABC- and double-hit sub-types, but not in normal CD34+ cells. Synergism is most likely multi-factorial, involving AKT inactivation/GSK3 activation, Bim up-regulation, Mcl-1 down-regulation, enhanced DNA damage, and is operative in vivo. Combined PI3K/mTOR and HDAC inhibition warrants further attention in DLBCL.

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Section: Discussionmentioning

confidence: 99%

PI3K/mTOR Inhibition Markedly Potentiates HDAC Inhibitor Activity in NHL Cells through BIM- and MCL-1–Dependent Mechanisms In Vitro and In Vivo

Rahmani

Aust

Benson

et al. 2014

Clinical Cancer Research

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“…[159,160] The upregulation of the PI3K/AKT/mTOR pathway can occur as a consequence of activating mutations in the FLT3 receptor, c-KIT receptor, NRAS , or KRASP . [35–37] In addition, upregulation can occur through abnormal autocrine/paracrine secretion of IGF-1 or vascular endothelial growth factor (VEGF), overexpression of PBKp100β, PI3Kp100δ or PDK1, or underexpression of protein phosphatase 2 (PP2A).…”

Section: Targeting Pi3k/akt/mtor In Pediatric Hematologic Malignanmentioning

confidence: 99%

“…[161–168] Unlike T-ALL, PTEN inactivation in AML is a very rare mechanism of AKT activation. [159,160] …”

Section: Targeting Pi3k/akt/mtor In Pediatric Hematologic Malignanmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Barrett¹,

Brown²,

Grupp³

et al. 2012

Pediatric Drugs

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The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin’s lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen. Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual- and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignancies, t...

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“…The PI3K/Akt/mTOR pathway is an important link in the regulation of cell proliferation, growth and survival [74]. It is known that the regulation of mTOR function is under the control of PI3k/Akt signaling pathway, activated by extracellular stimuli [75].…”

Section: Pi3k/akt/mtormentioning

confidence: 99%

Molecular Targeted Therapy in Melanoma: A Way to Reverse Resistance to Conventional Drugs

Maira¹,

Catania²,

Candido³

et al. 2012

CDD

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Cutaneous melanoma is the most aggressive skin cancer. Beside surgery, it is treated with chemotherapy and immunotherapy. However, many patients relapse after adjuvant therapy. The recent identification of several key molecular pathways implicated in the pathogenesis of melanoma is spreading development of a number of new translational targeted therapies which could play an important role in overcoming or minimizing resistance to chemotherapeutic drugs and proapoptotic therapies. This review summarizes environmental factors and the most significant molecular events involved in melanoma pathogenesis, disclosing mechanisms responsible for drug resistance and pointing out the clinical view for emerging targeted therapies. Standard therapies and an update on the current clinical trials are also described.

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The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients

Cited by 228 publications

References 153 publications

PI3K/mTOR Inhibition Markedly Potentiates HDAC Inhibitor Activity in NHL Cells through BIM- and MCL-1–Dependent Mechanisms In Vitro and In Vivo

PI3K/mTOR Inhibition Markedly Potentiates HDAC Inhibitor Activity in NHL Cells through BIM- and MCL-1–Dependent Mechanisms In Vitro and In Vivo

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Molecular Targeted Therapy in Melanoma: A Way to Reverse Resistance to Conventional Drugs

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