Further evaluation of PI3K/AKT/mTOR pathway inhibitors is required to confirm whether the patterns of sensitivity observed in preclinical studies can be applied in the clinic. Although many early-phase trials have independently failed to identify a distinct association between clinical response and the most common alterations in the PI3K pathway (PIK3CA mutation and PTEN loss), a pooled analysis of 140 patients with various breast and gynecologic cancers treated with different PI3K/AKT/mTOR inhibitors identified an increased rate of RECIST-defined clinical responses among patients with PIK3CA mutations (75). A follow-up study pooling 1,012 patients with diverse cancers treated with PI3K/AKT/mTOR pathway inhibitors also identified an increased rate of response among tumors with PIK3CA H1047R mutation, but not those with other PIK3CA mutations or concurrent PIK3CA and KRAS mutations (76). The findings of these association studies have sparked interest in the research community; however, additional ...
Poor outcome for patients with glioblastomas is often associated with radioresistance. PI3K/mTOR pathway deregulation has been correlated with radioresistance; therefore, PI3K/mTOR inhibition could render tumors radiosensitive. In this study, we show that NVP-BEZ235, a dual PI3K/mTOR inhibitor, potentiates the effects of irradiation in both adult and pediatric glioblastoma cell lines, resulting in early metabolic changes detected by nuclear magnetic resonance (NMR) spectroscopy. NVP-BEZ235 radiosensitises cells to X ray exposure, inducing cell death through the inhibition of CDC25A and the activation of p21(cip1)(CDKN1A). Lactate and phosphocholine levels, increased with radiation, are decreased after NVP-BEZ235 and combination treatment, suggesting that inhibiting the PI3K/mTOR pathway reverses radiation induced metabolic changes. Importantly, NVP-BEZ235 potentiates the effects of irradiation in a xenograft model of adult glioblastoma, where we observed a decrease in lactate and phosphocholine ...
Gafford, G. M., Parsons, R. G. and Helmstetter, F. J. (2013), Memory accuracy predicts hippocampal mTOR pathway activation following retrieval of contextual fear memory. Hippocampus, 23: 842-847. doi: 10.1002/hipo.22140 ...
The PI3K/mTOR pathway is one of the most commonly activated signaling pathway in human cancer. Many players in the PI3K pathway are either amplified, have undergone LOH, or are targeted by somatic or germline alterations (4). These observations led to the development of rapamycin and rapalogs, which are allosteric, irreversible inhibitors of mTORC1, for cancer treatment. Temsirolimus was approved for metastatic renal cell carcinoma in 2007, serving to validate the PI3K/mTOR pathway as a therapeutic target in cancer (17). Despite some success in selected tumor types, rapalogs generally showed very limited anticancer efficacy as single agents and mostly lead to cytostatic effects (18). Negative feedback loops involving S6K have been described to have dramatic effects on drug responses for mTORC1 inhibitors (19). Activated mTORC1 initiates a negative feedback cascade via S6K to downregulate PI3K activity. Treating tumors with rapalogs can result in increased PI3K/Akt activity leading to an enhanced ...
PI3K/Akt/mTOR inhibitors effect on CXCL12-induced MCL cell migration and invasionA, Primary MCL cells were preincubated with 5 μM everolimus, 1 μM NVP-BEZ235
The serine/threonine kinase mammalian target of rapamycin (mTOR) governs growth, metabolism, and aging in response to insulin and amino acids (aa), and is often activated in metabolic disorders and cancer. Much is known about the regulatory signaling network that encompasses mTOR, but surprisingly few direct mTOR substrates have been established to date. To tackle this gap in our knowledge, we took advantage of a combined quantitative phosphoproteomic and interactomic strategy. We analyzed the insulin- and aa-responsive phosphoproteome upon inhibition of the mTOR complex 1 (mTORC1) component raptor, and investigated in parallel the interactome of endogenous mTOR. By overlaying these two datasets, we identified acinus L as a potential novel mTORC1 target. We confirmed acinus L as a direct mTORC1 substrate by co-immunoprecipitation and MS-enhanced kinase assays. Our study delineates a triple proteomics strategy of combined phosphoproteomics, interactomics, and MS-enhanced kinase assays for the de ...
This study is the first to provide evidence for the efficacy of the novel dual PI3K/mTOR inhibitor NVP-BEZ235 in preclinical models of ovarian cancer. We demonstrate that NVP-BEZ235 effectively blocked PI3K/Akt/mTOR pathway signaling, decreased cell proliferation, and sensitized cells to cisplatin treatment. In immunocompetent mice with established ovarian tumor disease, oral administration of NVP-BEZ235 decreased pAkt, p4E-BP1, and Ki67 in tumor tissue, and resulted in significantly longer survival compared to control animals. Importantly, NVP-BEZ235 was effective in both platinum-sensitive and platinum-resistant cell models.. Targeting the PI3K/Akt/mTOR pathway in cancer disease has been a focus of drug development recently, but the optimal therapeutic strategy has yet to be identified. Prior studies including studies from our laboratory in preclinical models of ovarian cancer have mainly investigated the effects of either PI3K or mTOR inhibition alone (8, 33-40). For example, the mTOR ...
The introduction of high-throughput technologies in breast cancer enabled the recognition of groups with prognostic value, in which target-therapies can be applied. However, a relevant percentage of patients show no clinical benefit or incur in the development of acquired resistance. A possible solution could be the inhibition of pathways that are common in all tumor subtypes that have a proven role in carcinogenesis. Alterations of the serine-threonine kinase mammalian target of rapamycin (mTOR) signaling pathway are common in cancer and thus mTOR is being pursued as a therapeutic agent. Everolimus, a rapamycin analog, has already an established activity in the treatment of renal cell carcinoma. In this study, we proposed to evaluate the expression of activated mTOR in a large series of invasive carcinoma samples and cell lines, and its association with the four main molecular subtypes (Luminal A, Luminal B, HER2-overexpressing and Basal-like). We also aimed to evaluate the ability of ...
The use of these pharamaceutical rapalogs have been generally disappointing in human trials. One possible explanation for the disappointing results to date is that in human cancer, rapalogs predominately inhibit mTORC1, leading to increased PI3K and AKT signaling by preventing negative feedback through S6K and GRB10. 1 Recent studies have demonstrated that a number of natural products (or nutraceuticals) isolated from plants (e.g. fruits, vegetables, spices, nuts, legumes, herbs, etc.) also inhibit the mTOR pathway, and exhibit potent anticancer activities. These particular natural products are considered "natural rapalogs".. The Table below lists the identified natural substances that are considered natural rapalogs or mTOR inhibitors:. ...
The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates AKT, localizing it in the plasma membrane. AKT can have a number of downstream effects such as activating CREB, inhibiting p27, localizing FOXO in the cytoplasm, activating PtdIns-3ps, and activating mTOR which can affect transcription of p70 or 4EBP1. There are many known factors that enhance the PI3K/AKT pathway including EGF, shh, IGF-1, insulin, and CaM. The pathway is antagonized by various factors including PTEN, GSK3B, and HB9. In many cancers, this pathway is overactive, thus reducing apoptosis and allowing proliferation. This pathway is necessary, however, to promote growth and proliferation over differentiation of adult stem cells, neural stem cells specifically. It is the difficulty in finding an appropriate amount of proliferation versus ...
Clinical trial design. The success of tyrosine kinase inhibitors, such as erlotinib and imatinib, and the strong rationale to target the PI3K/Akt/mTOR pathway has fed optimism that inhibitors of serine/threonine kinases, such as PI3K, PDK-1, Akt, or mTOR, might have clinical use for cancer patients. Because these drugs are predicted to modulate a target and do not cause direct DNA damage like most standard chemotherapies, the design of clinical trials with PI3K/Akt/mTOR pathway inhibitors should reflect their biological activities. Based on numerous preclinical studies, pathway inhibitors are likely to be most effective in patients whose tumors bear activation of the pathway. Thus, phase I protocols with inhibitors of the PI3K/Akt/mTOR pathway should determine the biologically effective dose and the maximum tolerated dose and should determine the relationship between these doses. Although it can be argued that determining a tolerated biologically effective dose is sufficient for a targeted ...
Catalpol induces cell activity to promote axonal regeneration via the PI3K/AKT/mTOR pathway in vivo and in vitro stroke model
TY - JOUR. T1 - mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. AU - OReilly, Kathryn E.. AU - Rojo, Fredi. AU - She, Qing Bai. AU - Solit, David. AU - Mills, Gordon B.. AU - Smith, Debra. AU - Lane, Heidi. AU - Hofmann, Francesco. AU - Hicklin, Daniel J.. AU - Ludwig, Dale L.. AU - Baselga, Jose. AU - Rosen, Neal. PY - 2006/2/1. Y1 - 2006/2/1. N2 - Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity. We now ...
The molecular mechanisms underlying the quality and quantity of life extension appear to sometimes be orthogonal. For example, while resveratrol has continued to prove beneficial in reducing obesity, it has had less efficacy in extending lifespan. On the other hand, rapamycin and the chemically similar rapalogs extend lifespan across genera of life from yeast, to nematodes, to mice. Caloric restriction (CR) and bioavailable small molecules, which mimic a fasted state, upregulate autophagy, catabolism of fats over anabolism of carbohydrates, and decrease oxidative stress and inflammation. CR mimics are currently being investigated to elucidate the best dosage, route of administration, timing in life, where best to inhibit in the mTOR pathway, and effects of long-term use on mTORC1 verse mTORC2 complexes. Comparisons between rapamycin, resveratrol, and metformin targets, downstream pathway effects, dosage, and clinical trials will be discussed.
The PI3K pathway, which is commonly altered in numerous cancers (Liu et al., 2009a), has been identified as a promising target for the treatment of malignancies. Components of this signaling pathway, such as PI3K or mTOR, can be targeted by small molecules, and several inhibitors specific for one of these two kinases are being evaluated in patients (Engelman, 2009). Inhibitors of mTOR (mTORC1), referred to as rapalogs, have been approved for the treatment of cancers, and numerous dual PI3K/mTOR inhibitors are currently in clinical trials (Benjamin et al., 2011).. Preclinical pharmacokinetic studies provide key parameters during the discovery and the early stages of development of a compound. These parameters help to assess whether sufficient exposure can be achieved in further animal studies (efficacy and toxicology) and also are used to predict pharmacokinetic properties in humans. In addition, when integrated with efficacy data in PK-PD models, they can be used to estimate efficacious and ...
The PI3K/Akt/mTOR pathway controls many cellular processes that are important for the formation and progression of cancer, including apoptosis, transcription, translation, metabolism, angiogenesis, and cell cycle progression. Every major node of this signaling network is activated in a wide range of human tumors. Mechanisms for the pathway activation include activation of receptor tyrosine kinases (RTKs) upstream of PI3K, mutation or amplification of PIK3CA encoding p110α catalytic subunit of PI3K, mutation or loss of PTEN tumor suppressor gene, and mutation or amplification of Akt1. Once the pathway is activated, signaling through Akt can stimulate a series of substrates including mTOR which is involved in protein synthesis. Thus, inhibition of this pathway is an attractive concept for cancer prevention and/or therapy. Currently some mTOR inhibitors are approved for several indications, and there are several novel PI3K/Akt/mTOR inhibitors in clinical trials.. MCE owns a unique collection of ...
Our group has recently shown that proliferating mesenchymal cells (MC), obtained from BAL of BOS patients, express CD44 and that this expression correlates with mTOR expression and with in vitro proliferative rate. By these results we have designed an innovative approach based on biocompatible nanoparticles loaded with the mTOR inhibitor everolimus and functionalized with anti CD44 MoAb, for the selective targeting to the specific cells (targNP). Fluorescent labeled targNP have been used to assess cell uptake by confocal microscopy. Cell apoptosis/death (annexin V/7AAD) and proliferation (CFSE) were evaluated by flow cytometry. We used primary MC isolated from 2 BOS patients (grade 1 and 2) with the following phenotype: BOS 1: 85% CD90+ of which 33% co-expressing CD9; BOS2: 93% CD90+ with 38% co-expressing CD146, 25% CD9, and 38% both CD146 and CD9. Both MC samples were negative for CD45RO and CD34 and positive for CD44 (98%). TargNP were shown to adhere to membrane within 15 min and completely ...
SF1126 is a water soluble, small-molecule prodrug containing the pan-PI3K/mTOR inhibitor LY294002/SF1101 conjugated to the RGD-containing tetra-peptide SF1174 with potential antineoplastic and antiangiogenic activities. The targeting peptide SF1174 moiety of pan-PI3K/mTOR inhibitor SF1126 selectively binds to cell surface integrins and, upon cell entry, the agent is hydrolyzed to the active drug SF1101; SF1101 selectively inhibits all isoforms of phosphoinositide-3-kinase (PI3K) and other members of the PI3K superfamily, such as the mammalian target of rapamycin (mTOR) and DNA-PK.
Mammalian target of rapamycin (mTOR) has an important role in various biological processes in cells. In the present study, we investigated temporal changes in mTOR and phosphorylated-mTOR (p-mTOR) expressions in the rat hippocampal CA1 region following chronic cerebral hypoperfusion (CCH) induced by permanent bilateral common carotid arteries occlusion (2VO). The mTOR immunoreactivity in the pyramidal neurons and mTOR protein level in the hippocampal CA1 region were markedly decreased at 21 and 28 days after 2VO surgery. However, p-mTOR protein expression was significantly increased at 7 days following CCH but then decreased with time. The results indicate that mTOR and p-mTOR expressions change in the hippocampal CA1 region after 2VO surgery and that reduced expressions of mTOR and p-mTOR may be closely related to the CCH-induced neuronal damage in the hippocampal CA1 region ...
Although signaling from phosphatidylinositol 3-kinase (PI3K) and AKT to mechanistic target of rapamycin (mTOR) is prominently dysregulated in high-grade glial brain tumors, blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Allosteric mTOR inhibitors, such as rapamycin, incompletely block mTORC1 compared with mTOR kinase inhibitors (TORKi). Here, we compared RapaLink-1, a TORKi linked to rapamycin, with earlier-generation mTOR inhibitors. Compared with rapamycin and Rapalink-1, TORKi showed poor durability. RapaLink-1 associated with FKBP12, an abundant mTOR-interacting protein, enabling accumulation of RapaLink-1. RapaLink-1 showed better efficacy than rapamycin or TORKi, potently blocking cancer-derived, activating mutants of mTOR. Our study re-establishes mTOR as a central target in glioma and traces the failure of existing drugs to incomplete/nondurable inhibition of mTORC1.
In recent years numerous agents targeting the Ras/Raf/MEK or PI3K/AKT/mTOR pathways have entered clinical development, and dual targeting of these pathways is now been investigated clinically. It had been generally accepted, and shown, that direct inhibition of targets subject to mutational activation is effective (42), and this expectation has to some extent translated to cases in which the mutationally activated pathway is targeted at a nonmutated node (e.g., MEK inhibitors and Rapalogues). However, in some settings these initial observations have been shown to be more complicated, and the dependency of cancer cells for survival on both of these pathways is becoming better understood (25, 27, 43). In this study we report that dual targeting of the MEK and mTOR pathways, using well-tolerated schedules of the inhibitors selumetinib and AZD8055, respectively, results in enhanced antitumor efficacy across a panel of NSCLC and CRC xenograft and patient-derived explant models. Furthermore, ...
The serine-threonine kinase mammalian target of rapamycin (mTOR) is an important integrator of nutrient, cytokine and growth factor sensing in T cells and controls transcriptional programs that determine CD8+ cytotoxic T cell fate and trafficking. mTORC1 is inhibited by the drug rapamycin which is a powerful immunosuppressant used in the clinic in the context of organ transplantation. However, not much is known about the full extent of the role of mTOR signalling in CTL. We thus utilised high resolution quantitative mass spectrometry to define the mTOR regulated CTL proteome and map the abundance and isoform expression of more than 6700 proteins in CTL. The data provide unbiased analysis of how mTORC1 reprograms the transcriptional and proteome landscape of T cells. The results show that mTORC1 controls expression of approximately 700 proteins with equal numbers of up and down regulated proteins. This illustrates that mTORC1 inhibition does not lead to a general decreases in protein levels but ...
Antibody Sampler Kit for studying mTOR/mTOR (Ser2448) phosphate/PRAS40/PRAS40 (Thr246) phosphate/RagC/Raptor (Ser792) phosphate in the Protein Translation research area.
Cancer continues to be a leading cause death in the United States despite improved treatments. Cancerous lesions form after acquiring oncogenic driver mutations or losing tumor suppressor function in normal cells. Traditional therapies have included use of genotoxic substances that take advantage of the increased growth rate and loss of tumor suppressor function to cause cell death. One such drug is the anthracycline antibiotic doxorubicin (DOX). DOX interchelates into DNA and disrupts transcriptional machinery while also poisoning topoisomerase II. This results in single and double stranded DNA breaks, which if severe enough leads to either necrotic or apoptotic cell death. DOX has been very effective at treating several different cancers and is still widely used today however its clinical use is limited due to cumulative dose dependent cardiotoxicity. Therefore, combination therapy targeting survival pathways is utilized to minimize the cumulative dose of DOX without ameliorating its anti-tumor
The phosphatidylinositol-3-kinase /protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway plays an important role in cell proliferation, growth, and angiogenesis.
LY3023414 is a small molecule that has been shown in vitro to be a selective ATP-competitive inhibitor of PI3Kα and mTOR, DNA-PK, and other class I PI3K family members. In vitro, LY3023414 has demonstrated inhibitory activity against PI3K and mTOR in tumor cells, as well as antiproliferative activity and cell cycle effects. In addition, in vitro, LY3023414 inhibits the ability of PI3K and mTOR to phosphorylate substrates in the PI3K/mTOR pathway. LY3023414 is being investigated in a phase I clinical trial.
TY - JOUR. T1 - TBK1 provides context-selective support of the activated AKT/mTOR pathway in lung cancer. AU - Cooper, Jonathan M.. AU - Ou, Yi Hung. AU - McMillan, Elizabeth A.. AU - Vaden, Rachel M.. AU - Zaman, Aubhishek. AU - Bodemann, Brian O.. AU - Makkar, Gurbani. AU - Posner, Bruce A.. AU - White, Michael A.. PY - 2017/9/15. Y1 - 2017/9/15. N2 - Emerging observations link dysregulation of TANK-binding kinase 1 (TBK1) to developmental disorders, inflammatory disease, and cancer. Biochemical mechanisms accounting for direct participation of TBK1 in host defense signaling have been well described. However, the molecular underpinnings of the selective participation of TBK1 in a myriad of additional cell biological systems in normal and pathophysiologic contexts remain poorly understood. To elucidate the context-selective role of TBK1 in cancer cell survival, we employed a combination of broad-scale chemogenomic and interactome discovery strategies to generate data-driven mechanism-of-action ...
Minimization of immunosuppression and donor-specific tolerance to MHC-mismatched organ grafts are important clinical goals. The therapeutic potential of regulatory T cells (Tregs) has been demonstrated, but conditions for optimizing their in vivo function posttransplant in nonlymphocyte-depleted hosts remain undefined. In this study, we address mechanisms through which inhibition of the mammalian target of rapamycin (Rapa) synergizes with alloantigen-specific Treg (AAsTreg) to permit long-term, donor-specific heart graft survival in immunocompetent hosts. Crucially, immature allogeneic dendritic cells allowed AAsTreg selection in vitro, with minimal expansion of unwanted (Th17) cells. The rendered Treg potently inhibited T cell proliferation in an Ag-specific manner. However, these AAsTreg remained unable to control T cells stimulated by allogeneic mature dendritic cells, a phenomenon dependent on the release of proinflammatory cytokines. In vivo, Rapa administration reduced danger-associated ...
The mTOR complex 1 (mTORC1) controls cell growth in eukaryotes in response to nutrient signals such as amino acids and is commonly hyperactivated in cancer. Although upstream regulators of mTORC1, such as the PI3K and MEK pathways, are commonly mutated in cancer, these mutations do not correlate with response to mTOR-targeted therapy. Thomas, Zhang, and colleagues identified the small GTPase RAB1A, a regulator of ER-to-Golgi vesicular trafficking, as a mediator of mTORC1 signaling in response to amino acid stimulation. Loss of RAB1A in yeast and human cells decreased mTORC1 activity and conferred rapamycin sensitivity in a GTP- and amino acid-dependent manner, indicating that this regulatory mechanism is evolutionarily conserved. Amino acid stimulation promoted the interaction of RAB1A-GTP with mTORC1, and disruption of either RAB1A GTP binding or RAB1A localization to the ER/Golgi attenuated this interaction. Loss of RAB1A inhibited formation of the RAS homolog enriched in brain (RHEB)-mTORC1 ...
In this study, we provide novel evidence for a role of fetal liver mTOR signaling in regulating IGF-I bioavailability by modulating IGFBP-1 phosphorylation due to hypoxia - a key factor in the development of reduced fetal growth in utero. We utilized HepG2 cells in vitro and demonstrated a link between mTOR inhibition and hypoxia-induced IGFBP-1 phosphorylation. Using a biological assay for IGF-I receptor autophosphorylation, we demonstrated a functional significance for hypoxia-induced IGFBP-1 phosphorylation in reducing IGF-I bioactivity in vitro. Further, we have implicated a mechanistic link to increased CK2 activity within this regulation. We demonstrate that mTOR inhibition induced IGFBP-1 phosphorylation, which was not further enhanced by hypoxia, and that mTOR activation prevented hypoxia-induced IGFBP-1 phosphorylation. Together, we have identified a new mechanism involving mTOR inhibition during hypoxia by which IGFBP-1 phosphorylation, and thus IGF-I bioavailability, is regulated, and also
Rapamycin-insensitive companion of mTOR (Rictor) is encoded by the RICTOR gene in humans. Rictor shares homology with pianissimo from D. discoidieum, STE20p from S. pombe, and AVO3p from S. cerevisiae. It is involved in the control of the mammalian target of rapamycin (mTOR) and is a subunit of mTORC2. mTORC2 is activated by growth factors but, unlike mTORC1, the complex is insensitive to nutrient levels. Rictor interacts with mTOR kinase to modulate the phosphorylation of protein Kinase C alpha (PKC alpha) and the actin cytoskeleton. Rictor is also known as RPTOR independent companion of MTOR, complex 2; PIA, KIAA1999, AVO3 homolog, hAVO3, AVO3, MGC39830, and TORC2-specific protein AVO3.. ...
Rapamycin-insensitive companion of mTOR (Rictor) is encoded by the RICTOR gene in humans. Rictor shares homology with pianissimo from D. discoidieum, STE20p from S. pombe, and AVO3p from S. cerevisiae. It is involved in the control of the mammalian target of rapamycin (mTOR) and is a subunit of mTORC2. mTORC2 is activated by growth factors but, unlike mTORC1, the complex is insensitive to nutrient levels. Rictor interacts with mTOR kinase to modulate the phosphorylation of protein Kinase C alpha (PKC alpha) and the actin cytoskeleton. Rictor is also known as RPTOR independent companion of MTOR, complex 2; PIA, KIAA1999, AVO3 homolog, hAVO3, AVO3, MGC39830, and TORC2-specific protein AVO3.. ...
Knowledge of protein signalling pathways in the working cell is seen as a primary route to identifying and developing targeted medicines. In recent years there has been a growing awareness of the importance of the mTOR pathway, making it an attractive target for therapeutic intervention in several diseases. Within this pathway we have focused on S6 kinase 1 (S6K1), the downstream phosphorylation substrate of mTORC1, and specifically identify its juxtaposition with mTORC1. When S6K1 is co-expressed with raptor we show that S6K1 is translocated from the nucleus to the cytoplasm. By developing a novel biosensor we demonstrate in real-time, that phosphorylation and de-phosphorylation of S6K1 occurs mainly in the cytoplasm of living cells. Furthermore, we show that the scaffold protein raptor, that typically recruits mTOR substrates, is not always involved in S6K1 phosphorylation. Overall, we demonstrate how FRET-FLIM imaging technology can be used to show localisation of S6K1 phosphorylation in living cells
BEZ235 showed modest clinical activity and an unfavourable toxicity profile in patients with advanced and pretreated TCC; however, a minority of patients experienced a clinical benefit, suggesting that a complete blockade of the PI3K/mTOR axis could improve outcome in some specific patients. Further …
KRAS mutations in non-small-cell lung malignancy (NSCLC) patients are believed a poor predictive element and indicate poor response to anticancer remedies. combinations probably distinguishing wild-type and mutated KRAS malignancy cells in NSCLC, exploiting their different metabolic reactions to PI3K/akt/mTOR inhibitors. also to standard chemotherapeutics [5, 6]. Although KRAS is among the earliest recognised oncogenic motorists in NSCLC, effective focusing on remains a restorative challenge. All efforts to focus on it directly possess failed and KRAS is usually widely assumed to become undruggable [7]. Lately, a particular allosteric inhibitor of G12C mutated KRAS was explained, showing encouraging preclinical outcomes [8]. KRAS signaling is usually highly complicated and dynamic, interesting numerous downstream effectors, such as for example canonical Raf/Mek/Erk and PI3K/akt/mTOR signaling systems [9, 10]. KRAS mutations result in the activation of PI3Ks in lung tumor maintenance [11]. The ...
https://doi.org/10.18632/oncotarget.12811 Xianjuan Kou, Xingran Liu, Xianbing Chen, Jie Li, Xiaoqi Yang, Jingjing Fan, Yi Yang, Ning Chen
My bachelor thesis deals with the effect of mTOR pathway to different processes in the cell. In particular, it focuses on the influence of translation initiation. mTOR protein is part of two complexes, which occur in different organisms - mTORC1 and mTORC2. Eukaryotic initiation factor 4E (eIF4E) plays an important role in controlling translation initiation. The activity of eIF4E protein is regulated by family of repressor 4E-binding proteins (4E-BPs). Linking these proteins to eIF4E is regulated by their phosphorylation state. For the release of 4E-BP1 from eIF4E, phosphorylation must occur at four phosphorylation sites (Thr37, Thr46, Ser65 and Thr70). The study also covers some of the other events that occur in the mTOR pathway ...
The PI3K/AKT/mTOR pathway is critical for cancer cell proliferation and survival. Inhibition of this pathway has been clinically proven to be effective in cancer therapy. For example, the inhibitor of mTOR rapamycin has been approved by FDA for renal cancer therapy and Everolimus, a rapamycin homologue, has recently been approved by FDA for metastatic breast cancer therapy. A number of inhibitors of this pathway have been developed by a number of companies and are currently in phase I and phase II clinical trials for cancer therapy.. Although these inhibitors are expected to improve the outcomes of cancer patients, the therapeutic effect will be very limited. The reason is that inhibition of this pathway will cause feedback activation of other oncogenic pathways, which will in turn drive cell proliferation and survival. One example of this is the failure of rapamycin in randomized clinical trials for cancer because of feedback activation of PI3K/AKT. Scientific studies have also shown that ...
The Lamming laboratory is primarily focused on understanding the physiological role played by the mechanistic target of rapamycin (mTOR), a protein kinase that, through a diverse set of substrates, regulates cellular processes including growth, metabolism, and aging. Recent work hasshown that rapamycin, an inhibitor of mTOR signaling, can promote health and longevity in model organisms including mammals. As detailed by Dr. Lamming in a recent review article - Rapalogs and mTOR inhibitors as anti-aging therapeutics - understanding and manipulating the mTOR signaling pathway may provide insight into the treatment of age-related diseases, including diabetes, Alzheimers disease, and cancer.. ...
The PI3K-AKT-mTOR pathway is hyperactivated in many human cancers, including RCC. The moderate clinical benefit of the mTOR inhibitor observed in several human cancer clinical trials and the mTORC1 inhibition-mediated feedback activation of PI3K-AKT have prompted ideas for inhibiting the upstream PI3K-AKT in cancer treatment (28). However, the relief of feedback regulation and the resulting activation of other oncogenic signaling pathways caused by PI3K-AKT inhibition likely will limit the clinical utilization of such inhibitors in cancer treatment.. Using NVP-BEZ235 as a pharmacologic approach to inhibit PI3K, our study reveals a novel mechanism of PI3K inhibition-induced feedback regulation in RCC cells, which involves FoxO-mediated Rictor upregulation and AKT reactivation via Ser473 phosphorylation. Specifically, our data show that, although short-term treatment of NVP-BEZ235 leads to immediate PI3K-AKT inactivation and FoxO activation, long-term treatment of NVP-BEZ235 leads to FoxO binding ...
mTOR is an intracellular serine-threonine kinase downstream of the phosphatidyl inositol 3′ kinase (PI3K)-AKT signaling pathway. Under physiologic conditions the PI3K-AKT-mTOR signaling pathway plays a major role in regulating cell growth, proliferation, motility, and survival, and cellular nutrient and energy levels, protein synthesis, autophagy, transcription, and redox status. mTOR integrates multiple upstream signals, including growth factors (e.g., EGF and IGF-1/2), and mitogens. Interestingly, mTOR is also involved in angiogenesis, regulating the translation and activity of hypoxia-inducible factor 1α (HIF1α), which is related to VEGF expression under hypoxic conditions.. Hyperactive mTOR signaling is a key participant in development, growth, and proliferation in about 50% of all human tumors. mTOR acts as the catalytic subunit of 2 distinct complexes. mTOR complex 1 (mTORC1) consists of mTOR, the target of the rapamycin complex subunit LST8 (LST8, also known as GβL), the proline-rich ...
In my PNAS Inaugural Article, I describe the development of the mTOR field, starting with efforts to understand the mechanism of action of the drug rapamycin, which ∼25 y ago led to the discovery of the mTOR protein kinase. I focus on insights that we have contributed and on work that has been particularly influential to me, as well as provide some personal reflections and stories. We now appreciate that, as part of two distinct complexes, mTORC1 and mTORC2, mTOR is the major regulator of growth (mass accumulation) in animals and is the key link between the availability of nutrients in the environment and the control of most anabolic and catabolic processes ...
B-cell activating factor (BAFF) is involved in not only physiology of normal B cells, but also pathophysiology of aggressive B cells related to malignant and autoimmune diseases. Rapamycin, a lipophilic macrolide antibiotic, has recently shown to be effective in the treatment of human lupus erythematosus. However, how rapamycin inhibits BAFF-stimulated B-cell proliferation and survival has not been fully elucidated.
Background: Mammalian target of rapamycin (mTOR) inhibitors are found in a variety of malignancies. (CI 95%, 1.54C4.41, control (RR=1.97; 95% CI, 0.97C4.03, all other malignancies. The RR of all-grade contamination in patients treated with RCC was 1.84 (95% CI, 1.53C2.21; phase III trials. There were no statistically significant differences between the phase subgroups for either grade (all-grade 33.1% Motzer et al, 2010), the RECORD-1 Study Group subsequently published recommendations for the management of infections and other adverse events according to the grade buy Lafutidine of the event (Porta et al, 2011; Ravaud, 2011). These recommendations can be used by clinicians to effectively manage treatment-related infections. Fungal infections such as Candida and Aspergillosis, mycobacterial infections such as tuberculosis, and viral infections such as hepatitis and herpes occurred in the studies used in our analysis and were reported in the prescribing information (Novartis, 2012; Pfizer, 2012). ...
Blockade of mammalian target of rapamycin (mTOR) is a promising area in breast cancer therapy. However, in clinical trials, objective response rate with mTOR inhibitor monotherapy in breast cancer...
The Young Oncologists Journal Club is an initiative from the European Society from Medical Oncology. Read the latest article on sarcomas.
Mammalian cell growth is tightly linked to adequate supplies of growth factors and nutrients, including glucose and amino acids. The mechanistic target of rapamycin complex 1 (mTORC1) functions as a coincidence detector that supports anabolic metabolism when convergent growth factor- and nutrient-derived signals trigger mTORC1 kinase activation. Conversely, nutrient starvation suppresses mTORC1 activity and triggers a shift to catabolic pathways, such as autophagy, to support cell survival under austere conditions. An elaborate signaling apparatus has evolved to harmonize mTORC1 kinase activation and protein synthesis with supplies of leucine and other amino acids (1). Earlier findings implicated the leucyl-transfer RNA (tRNA) synthetase 1 (LARS1) as a proximate sensor of leucine availability (2). On page 205 of this issue, Yoon et al. (3) report that glucose modulates the functions of LARS1 in leucine sensing and disposition, thereby coordinating leucine-dependent mTORC1 activation and protein ...
Regulation of glucose homeostasis by insulin depends on β-cell growth and function. Nutrients and growth factors stimuli converge on the conserved protein kinase mechanistic target of rapamycin (mTOR), existing in two complexes mTORC1 and mTORC2. To understand the functional relevance of mTOR enzymatic activity in β-cell development and in glucose homeostasis, we generated mice overexpressing either one or two copies of a kinase-dead mTOR mutant (KD-mTOR) transgene exclusively in β-cells. We examined glucose homeostasis and β-cell function of these mice in control chow and in high-fat diet (HFD). Mice with two copies of the transgene (RIPCre;KD-mTOR (Homo)) develop glucose intolerance due to a defect in β-cell function without alterations in β-cell mass in control chow. Islets from RIPCre;KD-mTOR (Homo) mice showed reduced mTORC1 and mTORC2 signaling along with transcripts and protein levels of Pdx-1. Islets with reduced mTORC2 signaling in their β-cells (RIPCre;Rictorfl/fl) also showed ...
The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth and proliferation that is often aberrantly activated in cancer, as...
DEPTOR [DEP-domain-containing and mTOR (mammalian target of rapamycin)-interacting protein] is a modulator of mTOR signalling that binds to mTORC (mTOR complex) 1 and mTORC2. However, to date, the precise functions of DEPTOR are not fully elucidated,