Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia

Evangelisti, Camilla; Ricci, Francesca; Tazzari, Pier Luigi; Tabellini, Giovanna; Battistelli, Michela; Falcieri, Elisabetta; Chiarini, Francesca; Bortul, Roberta; Melchionda, Fraia; Pagliaro, Pasqualepaolo; Pession, Andrea; McCubrey, James A.; Martelli, Alberto M.

doi:10.1038/leu.2011.20

Cited by 90 publications

(77 citation statements)

References 46 publications

(54 reference statements)

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“…182 Intriguingly, rapamycin was not as effective as the active-site mTOR inhibitors. 183 PTEN plays critical roles in regulating cell cycle progression in HSC and other cells. PTEN influences the decision of whether the cells remain in quiescence (G 0 ) or enter G 1 and also controls the subsequent speed of proliferation.…”

Section: Mtorc1-hif Drug Resistancementioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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Section: Mtorc1-hif Drug Resistancementioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

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“…[29,154] Furthermore, the dual mTORC1/2 inhibitors PP242 and OSI-027 are very active in vitro against pre-clinical models of pre-T-ALL (cell lines and primary cells) and are superior to rapalogs as these agents successfully inactivate AKT and mTOR. [156] BEZ235, an inhibitor of mTORC1/2 and PI3K, was also shown to be very active against pre-T-ALL in vitro, inactivating both AKT and mTOR. [95] Preliminary studies demonstrate similar results with BEZ235 in pre-B-ALL in vitro and in vivo.…”

Section: Acute Lymphoblastic Leukemiamentioning

confidence: 99%

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

et al. 2012

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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 malignanc...

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“…We have recently demonstrated that inhibition of mTORC1-mediated oncogenic protein translation occurs also in T-ALL cells treated with mTORC1/mTORC2 ATP-competitive inhibitors, but not with rapamycin. 12 Here, we show that in T-ALL cell lines and patient primary cells, the LKB1/ AMPK tumor-suppressor pathway is functional and can be activated by metformin treatment. Accordingly, metformin displayed a strong cytotoxic activity against both T-ALL cell lines and lymphoblasts from the T-ALL patients but barely affected the proliferation of peripheral blood CD4 þ T-lymphocytes from healthy donors.…”

Section: Introductionmentioning

confidence: 99%

“…12 Polysome analysis, [ 3 H]-leucine incorporation and 7methyl-GTP cap affinity assay These were performed as reported elsewhere. 12 Quantitative real-time PCR on mRNAs polysome fractions…”

Section: Transmission Electron Microscope Analysismentioning

confidence: 99%

“…10 Upregulated mTORC1 activity within cancer cells increases the synthesis of many oncogenic proteins controlled at the translation initiation level, through the phosphorylation of the physiologic translation repressor 4E-BP1 at multiple residues. 11, 12 An important regulator of the mTORC1-dependent translation process is the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) axis. LKB1 is a serine/threonine protein kinase encoded by the STK11 gene, originally identified as the gene mutated in the rare autosomal dominant human genetic disorder, Peutz-Jeghers syndrome.…”

Section: Introductionmentioning

confidence: 99%

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AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

et al. 2011

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The mammalian target of rapamycin (mTOR) serine/threonine kinase is the catalytic subunit of two multi-protein complexes, referred to as mTORC1 and mTORC2. Signaling downstream of mTORC1 has a critical role in leukemic cell biology by controlling mRNA translation of genes involved in both cell survival and proliferation. mTORC1 activity can be down-modulated by upregulating the liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) pathway. Here, we have explored the therapeutic potential of the anti-diabetic drug, metformin (an LKB1/AMPK activator), against both T-cell acute lymphoblastic leukemia (T-ALL) cell lines and primary samples from T-ALL patients displaying mTORC1 activation. Metformin affected T-ALL cell viability by inducing autophagy and apoptosis. However, it was much less toxic against proliferating CD4(+) T-lymphocytes from healthy donors. Western blot analysis demonstrated dephosphorylation of mTORC1 downstream targets. Unlike rapamycin, we found a marked inhibition of mRNA translation in T-ALL cells treated with metformin. Remarkably, metformin targeted the side population of T-ALL cell lines as well as a putative leukemia-initiating cell subpopulation (CD34(+)/CD7(-)/CD4(+)) in patient samples. In conclusion, metformin displayed a remarkable anti-leukemic activity, which emphasizes future development of LKB1/AMPK activators as clinical candidates for therapy in T-ALL. Leukemia (2012) 26, 91-100; doi:10.1038/leu.2011.269; published online 4 October 201

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Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia

Cited by 90 publications

References 46 publications

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

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

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

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