Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms that regulate the growth and survival of acute myeloid leukemia (AML) cells are largely unknown. We hypothesized that constitutive activation of phosphatidyl-inositide 3 kinase (PI3 kinase) could regulate survival in primary cells from patients with AML. Here we demonstrate that Akt, a critical substrate of PI3 kinase, is activated in AML blasts. In a short-term culture system, most AML patient samples showed a dose-dependent decrease in survival after incubation with the PI3 kinase inhibitor LY294002. This decrease in survival was partially due to the induction of apoptosis. Furthermore, we have shown that p70 S6 kinase and 4EBP-1, downstream mediators of Akt signaling, also are phosphorylated in AML blasts. Phosphorylation of these proteins is inhibited by the mTOR inhibitor RAD001. Incubation of AML blasts with RAD001 induces only a small decrease in survival of the cells; however, when combined with Ara-C, RAD001 enhances the toxicity of Ara-C. These results demonstrate that constitutive activation of the PI3 kinase pathway is necessary for the survival of AML blasts and that targeting of this pathway with pharmacologic inhibitors may be of clinical benefit in treatment of AML.
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PMID:Survival of acute myeloid leukemia cells requires PI3 kinase activation. 1270 6

Abnormal protein tyrosine kinases (PTKs) cause many human leukemias. For example, BCR/ABL causes chronic myelogenous leukemia (CML), whereas FLT3 mutations contribute to the pathogenesis of acute myelogenous leukemia. The ABL inhibitor Imatinib (Gleevec, STI571) has remarkable efficacy for treating chronic phase CML, and FLT3 inhibitors (e.g., PKC412) show similar promise in preclinical studies. However, resistance to PTK inhibitors is a major emerging problem that may limit long-term therapeutic efficacy. Development of rational combination therapies will probably be required to effect cures of these and other neoplastic disorders. Here, we report that the mTOR inhibitor rapamycin synergizes with Imatinib against BCR/ABL-transformed myeloid and lymphoid cells and increases survival in a murine CML model. Rapamycin/Imatinib combinations also inhibit Imatinib-resistant mutants of BCR/ABL, and rapamycin plus PKC412 synergistically inhibits cells expressing PKC412-sensitive or -resistant leukemogenic FLT3 mutants. Biochemical analyses raise the possibility that inhibition of 4E-BP1 phosphorylation may be particularly important for the synergistic effects of PTK inhibitor/rapamycin combinations. Addition of a mitogen-activated protein kinase kinase inhibitor to rapamycin or rapamycin plus PTK inhibitor further increases efficacy. Our results suggest that simultaneous targeting of more than one signaling pathway required by leukemogenic PTKs may improve the treatment of primary and relapsed CML and/or acute myelogenous leukemia caused by FLT3 mutations. Similar strategies may be useful for treating solid tumors associated with mutant and/or overexpressed PTKs.
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PMID:Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. 1497 43

Interactions between the Chk1 inhibitor UCN-01 and the farnesyltransferase inhibitor L744832 were examined in human leukemia cells. Combined exposure of U937 cells to subtoxic concentrations of UCN-01 and L744832 resulted in a dramatic increase in mitochondrial dysfunction, apoptosis, and loss of clonogenicity. Similar interactions were noted in other leukemia cells (HL-60, Raji, Jurkat) and primary acute myeloid leukemia (AML) blasts. Coadministration of L744832 blocked UCN-01-mediated phosphorylation of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK), leading to down-regulation of phospho-cyclic adenosine monophosphate responsive element-binding protein (phospho-CREB) and -p90(RSK) and activation of p34(cdc2) and stress-activated protein kinase/ERK kinase/c-Jun N-terminal kinase (SEK/JNK). Combined treatment also resulted in pronounced reductions in levels of phospho-Akt, -glycogen synthase kinase-3 (-GSK-3), -p70(S6K), -mammalian target of rapamycin (-mTOR), -forkhead transcription factor (-FKHR), -caspase-9, and -Bad. Ectopic expression of Bcl-2 or Bcl-xL but not dominant-negative caspase-8 blocked UCN-01/L744832-mediated mitochondrial dysfunction and apoptosis but did not prevent activation of p34(cdc2) and JNK or inactivation of MEK/ERK and Akt. Enforced expression of myristoylated Akt but not constitutively active MEK significantly attenuated UCN-01/L744832-induced apoptosis. However, dual transfection with Akt and MEK resulted in further protection from UCN-01/L744832-mediated lethality. Finally, down-regulation of JNK1 by siRNA significantly reduced the lethality of the UCN-01/L744832 regimen. Together, these findings suggest that farnesyltransferase inhibitors interrupt the cytoprotective Akt and MAPK pathways while reciprocally activating SAPK/JNK in leukemia cells exposed to UCN-01 and, in so doing, dramatically increase mitochondria-dependent apoptosis.
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PMID:Farnesyltransferase inhibitors interact synergistically with the Chk1 inhibitor UCN-01 to induce apoptosis in human leukemia cells through interruption of both Akt and MEK/ERK pathways and activation of SEK1/JNK. 1549 23

The mammalian target of rapamycin (mTOR) is a key regulator of growth and survival in many cell types. Its constitutive activation has been involved in the pathogenesis of various cancers. In this study, we show that mTOR inhibition by rapamycin strongly inhibits the growth of the most immature acute myeloid leukemia (AML) cell lines through blockade in G0/G1 phase of the cell cycle. Accordingly, 2 downstream effectors of mTOR, 4E-BP1 and p70S6K, are phosphorylated in a rapamycin-sensitive manner in a series of 23 AML cases. Interestingly, the mTOR inhibitor markedly impairs the clonogenic properties of fresh AML cells while sparing normal hematopoietic progenitors. Moreover, rapamycin induces significant clinical responses in 4 of 9 patients with either refractory/relapsed de novo AML or secondary AML. Overall, our data strongly suggest that mTOR is aberrantly regulated in most AML cells and that rapamycin and analogs, by targeting the clonogenic compartment of the leukemic clone, may be used as new compounds in AML therapy.
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PMID:Antileukemic activity of rapamycin in acute myeloid leukemia. 1555 Apr 88

FLT3 (fms-like tyrosine kinase 3) is constitutively activated in about 30% of patients with acute myeloid leukemia (AML) and represents a disease-specific molecular marker. Although FLT3-LM (length mutation) and TKD (tyrosine kinase domain) mutations have been considered to be mutually exclusive, 1% to 2% of patients carry both mutations. However, the functional and clinical significance of this observation is unclear. We demonstrate that FLT3-ITD-TKD dual mutants induce drug resistance toward PTK inhibitors and cytotoxic agents in in vitro model systems. As molecular mechanisms of resistance, we found that FLT3-ITD-TKD mutants cause hyperactivation of STAT5 (signal transducer and activator of transcription-5), leading to upregulation of Bcl-x(L) and RAD51 and arrest in the G(2)M phase of the cell cycle. Overexpression of Bcl-x(L) was identified as the critical mediator of drug resistance and recapitulates the PTK inhibitor and daunorubicin-resistant phenotype in FLT3-ITD cells. The combination of rapamycin, a selective mTOR inhibitor, and FLT3 PTK inhibitors restored the drug sensitivity in FLT3 dual mutant-expressing cells. Our data provide the molecular basis for understanding clinical FLT3 PTK inhibitor resistance and point to therapeutical strategies to overcome drug resistance in patients with AML.
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PMID:FLT3-ITD-TKD dual mutants associated with AML confer resistance to FLT3 PTK inhibitors and cytotoxic agents by overexpression of Bcl-x(L). 1562 38

Acute myeloid leukemia (AML) cells can be differentiated into dendritic cells (DCs) using appropriate combinations of cytokines but generation of autologous antileukemic cytotoxic T cells using leukemic DCs remains difficult. Transduction by adenoviral vectors has been reported to induce efficient maturation of monocyte-derived DCs but AML cells are generally resistant to adenoviral gene transfer. In this study we tested the effects of adenoviral TNF-alpha gene transfer on maturation of AML cells using the fiber-modified AdTNF.F(pK7) adenovirus. All samples expressed high and sustained levels of TNF-alpha following transduction. AdTNF.F(pK7) induced significantly greater maturation of AML cells into antigen-presenting cells (APC) than did recombinant TNF-alpha or control adenoviral vector. Maturation of leukemic cells into APCs was mediated at least partially via a PI3K/mTOR pathway, as the inhibitors LY294002, wortmannin, and rapamycin inhibited the maturation effect induced by the AdTNF.F(pK7) adenovirus. In addition, CD8+ T cells expanded with AdTNF.F(pK7)-transduced AML cells showed greater expansion and specific CD8+ CTL activity against autologous AML cells than T cells expanded by other means. Thus, fiber-modified adenoviral vectors encoding TNF-alpha are able to maturate AML cells into APCs with high efficacy and reproducibility, providing a useful tool to generate efficiently specific CD8+ CTLs against leukemic disease.
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PMID:Induction of leukemia-specific CD8+ cytotoxic T cells with autologous myeloid leukemic cells maturated with a fiber-modified adenovirus encoding TNF-alpha. 1592 66

Acute myeloid leukemia cells have constitutive activation of phosphatidylinositol 3(PI3) kinase and require PI3 kinase activation for survival; however, the function of the PI3 kinase pathway in the survival of leukemic cells is poorly defined. We have studied the role of one PI3 kinase substrate, mTOR (mammalian target of rapamycin), in primary leukemic cells. In initial experiments, we have defined a novel growth medium that improves survival of acute myeloid leukemia (AML) blasts in long-term suspension culture and the survival of leukemic stem cells in short-term cultures. Inhibition of mTOR using rapamycin leads to a modest decrease in cell survival after 2 days of incubation with more significant decrease in survival after 7 days of culture. However, when rapamycin is added to etoposide in 2-day cultures, there is a dramatic increase in the cytotoxicity of etoposide against AML blasts. Furthermore, etoposide consistently decreased the engraftment of AML cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) animals, and this effect was enhanced by coincubation with rapamycin, demonstrating that mTOR regulates survival of AML stem cells after etoposide treatment. These results suggest that rapamycin in combination with etoposide-based chemotherapy may be efficacious in the treatment of AML.
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PMID:mTOR regulates cell survival after etoposide treatment in primary AML cells. 1615 Sep 37

The mTOR (mammalian target of rapamycin) serine threonine kinase is involved in the regulation of the cell cycle, apoptosis and angiogenesis. mTOR inhibitors (rapamycin, or analogues such as CCI-779, RAD001, AP23573), which have been shown to have a potent anti-neoplastic effect in many solid tumor models, are now being used in clinical trials. Recent data have shown that the mTOR pathway is also aberrantly activated in hematological malignancies including acute myeloid leukemia (AML). This disease still has a bad prognosis and new therapeutic strategies are required. Rapamycin, used at low concentrations, induces the profound inhibition of AML cell clonogenic properties in 60% of cases while sparing their normal counterparts. Moreover, clinical responses have been achieved in poor-risk AML patients. In this review, we discuss the possible mechanisms of mTOR activation, the mechanisms involved in the inhibition of cell proliferation by rapamycin, the possible resistance mechanisms and ways of improving rapamycin efficacy in the context of AML.
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PMID:mTOR, a new therapeutic target in acute myeloid leukemia. 1620 24

The heterogeneity of acute myeloid leukemia (AML) has been established by many new insights into the diagnosis, pathogenesis, clinical manifestations, treatment, and prognosis of patients with AML. Morphology remains the foundation for the diagnosis. However, additional diagnostic studies, including immunophenotyping, cytogenetic evaluation, and molecular genetic studies, are necessary to develop treatments because specific subtypes of AML can now be approached with targeted therapy. Acute promyelocytic leukemia (APL), defined by a single molecular abnormality, is now treated with specific targeted therapy, all-trans retinoic acid (ATRA), and this subtype of AML is now highly curable. Currently, a number of agents have been explored in AML, including anti-CD33 antibodies and immunoconjugate drugs, inhibitors of multidrug resistance proteins, farnesyl transferase inhibitors, tyrosine kinase inhibitors, anti-Bcl-2 transcription agents, and inhibitors of mammalian target of rapamycin (mTOR). New alkylating agents, and purine analogs such as Cloretazine and clofarabine, affect DNA and ribonucleoside reductases, respectively. These agents have shown promise in small studies. Large phase III studies will address whether these are effective in inducing complete responses. Combining targeted agents with chemotherapy may improve the response rates. The plan for the future is to find therapeutic strategies that are specific for patients based on the specific biology of the disease. Future studies will investigate combinations of targeted therapies with each other and with chemotherapies to maximize the inhibition of multiple pathways present in AML. Additionally, evaluation of the identified prognostic factors and gene mutations will enable further pathologic classification of patients with AML.
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PMID:New agents for the treatment of acute myeloid leukemia. 1651 28

Despite important progress in the therapy of acute myeloid leukaemia (AML) most patients relapse and die from the disease, underlying the need for potent and more specific drugs for the treatment of this pathology. Recently, we demonstrated that the PI3-kinase-Akt-mTOR (mammalian target of rapamycin) pathway is constitutively activated in about 60% of AML patients cells. In vitro, low doses of the specific inhibitor of mTOR, rapamycin, block the phosphorylation of the classical targets of this kinase and inhibit the proliferation of leukemic progenitors without affecting the growth of normal haematopoietic progenitors. The results of this preclinical study led us to investigate the activity of rapamycin in relapsed, refractory, or poor-risk AML patients. The results of this study will be discussed in the review.
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PMID:[The PI3K/Akt/mTOR pathway: a new therapeutic target in the treatment of acute myeloid leukemia]. 1677 21


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