scholarly journals The Role of mTOR Signaling as a Therapeutic Target in Cancer

2021 ◽  
Vol 22 (4) ◽  
pp. 1743
Author(s):  
Nadezhda V. Popova ◽  
Manfred Jücker
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Genetic Alterations ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Cell Processes ◽  
And Function ◽  
Available Information ◽  
Mtor Complex 1

The aim of this review was to summarize current available information about the role of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling in cancer as a potential target for new therapy options. The mTOR and PI3K/AKT/mTORC1 (mTOR complex 1) signaling are critical for the regulation of many fundamental cell processes including protein synthesis, cell growth, metabolism, survival, catabolism, and autophagy, and deregulated mTOR signaling is implicated in cancer, metabolic dysregulation, and the aging process. In this review, we summarize the information about the structure and function of the mTOR pathway and discuss the mechanisms of its deregulation in human cancers including genetic alterations of PI3K/AKT/mTOR pathway components. We also present recent data regarding the PI3K/AKT/mTOR inhibitors in clinical studies and the treatment of cancer, as well the attendant problems of resistance and adverse effects.

Role of PRAS40 in Akt and mTOR signaling in health and disease

2012 ◽  
Vol 302 (12) ◽  
pp. E1453-E1460 ◽  
Author(s):  
Claudia Wiza ◽  
Emmani B. M. Nascimento ◽  
D. Margriet Ouwens
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Cellular Growth ◽  
S6 Kinase ◽  
Binding Partners ◽  
Health And Disease ◽  
Mtor Complex 1 ◽  
Mtor Activity

The proline-rich Akt substrate of 40 kDa (PRAS40) acts at the intersection of the Akt- and mammalian target of rapamycin (mTOR)-mediated signaling pathways. The protein kinase mTOR is the catalytic subunit of two distinct signaling complexes, mTOR complex 1 (mTORC1) and mTORC2, that link energy and nutrients to the regulation of cellular growth and energy metabolism. Activation of mTOR in response to nutrients and growth factors results in the phosphorylation of numerous substrates, including the phosphorylations of S6 kinase by mTORC1 and Akt by mTORC2. Alterations in Akt and mTOR activity have been linked to the progression of multiple diseases such as cancer and type 2 diabetes. Although PRAS40 was first reported as substrate for Akt, investigations toward mTOR-binding partners subsequently identified PRAS40 as both component and substrate of mTORC1. Phosphorylation of PRAS40 by Akt and by mTORC1 itself results in dissociation of PRAS40 from mTORC1 and may relieve an inhibitory constraint on mTORC1 activity. Adding to the complexity is that gene silencing studies indicate that PRAS40 is also necessary for the activity of the mTORC1 complex. This review summarizes the regulation and potential function(s) of PRAS40 in the complex Akt- and mTOR-signaling network in health and disease.

scholarly journals mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?

2020 ◽  
Author(s):  
Shi-Yong Sun
Keyword(s):  
Cancer Therapy ◽  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Targeted Cancer Therapy ◽  
Biological Functions ◽  
New Findings ◽  
Survival Signaling ◽  
Mtor Complex 1

Abstract The mammalian target of rapamycin (mTOR) critically regulates several essential biological functions, such as cell growth, metabolism, survival, and immune response by forming two important complexes, namely, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). mTOR signaling is often dysregulated in cancers and has been considered an attractive cancer therapeutic target. Great efforts have been made to develop efficacious mTOR inhibitors, particularly mTOR kinase inhibitors, which suppress mTORC1 and mTORC2; however, major success has not been achieved. With the strong scientific rationale, the intriguing question is why cancers are insensitive or not responsive to mTOR-targeted cancer therapy in clinics. Beyond early findings on induced activation of PI3K/Akt, MEK/ERK, and Mnk/eIF4E survival signaling pathways that compromise the efficacy of rapalog-based cancer therapy, recent findings on the essential role of GSK3 in mediating cancer cell response to mTOR inhibitors and mTORC1 inhibition-induced upregulation of PD-L1 in cancer cells may provide some explanations. These new findings may also offer us the opportunity to rationally utilize mTOR inhibitors in cancer therapy. Further elucidation of the biology of complicated mTOR networks may bring us the hope to develop effective therapeutic strategies with mTOR inhibitors against cancer.

scholarly journals Targeting AKT/mTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials

2020 ◽  
Vol 21 (9) ◽  
pp. 3285 ◽  
Author(s):  
Choudhary Harsha ◽  
Kishore Banik ◽  
Hui Li Ang ◽  
Sosmitha Girisa ◽  
Rajesh Vikkurthi ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Therapeutic Interventions ◽  
Treatment Modalities ◽  
Disease Heterogeneity ◽  
Mesenchymal Transition

Oral cancer (OC) is a devastating disease that takes the lives of lots of people globally every year. The current spectrum of treatment modalities does not meet the needs of the patients. The disease heterogeneity demands personalized medicine or targeted therapies. Therefore, there is an urgent need to identify potential targets for the treatment of OC. Abundant evidence has suggested that the components of the protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway are intrinsic factors for carcinogenesis. The AKT protein is central to the proliferation and survival of normal and cancer cells, and its downstream protein, mTOR, also plays an indispensable role in the cellular processes. The wide involvement of the AKT/mTOR pathway has been noted in oral squamous cell carcinoma (OSCC). This axis significantly regulates the various hallmarks of cancer, like proliferation, survival, angiogenesis, invasion, metastasis, autophagy, and epithelial-to-mesenchymal transition (EMT). Activated AKT/mTOR signaling is also associated with circadian signaling, chemoresistance and radio-resistance in OC cells. Several miRNAs, circRNAs and lncRNAs also modulate this pathway. The association of this axis with the process of tumorigenesis has culminated in the identification of its specific inhibitors for the prevention and treatment of OC. In this review, we discussed the significance of AKT/mTOR signaling in OC and its potential as a therapeutic target for the management of OC. This article also provided an update on several AKT/mTOR inhibitors that emerged as promising candidates for therapeutic interventions against OC/head and neck cancer (HNC) in clinical studies.

The role of mTOR inhibitors in targeting a putative cancer stem cell-like population in esophageal cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 43-43
Author(s):  
Da Wang ◽  
Roland Chiu ◽  
John Theodorus Plukker ◽  
Robert P. Coppes
Keyword(s):  
Esophageal Cancer ◽  
Cell Lines ◽  
Mammalian Target Of Rapamycin ◽  
Neoadjuvant Chemoradiotherapy ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Tumor Biopsy ◽  
Sphere Formation ◽  
Dose Dependent

43 Background: Despite modern advances in the treatment of esophageal cancer (EC), using neoadjuvant chemoradiotherapy (CRT) and esophagectomy, most patients face poor outcome. Growing evidence indicates that cancer stem cells (CSCs) might contribute to the poor prospects. CSCs are usually resistant to CRT and ultimately can generate a new tumor. The mammalian target of rapamycin (mTOR) pathway is associated with cancer stemness. However, its role in EC CSC-like populations needs to be elucidated. Here, we investigate the role of mTOR pathway on the stemness of a putative CSC-like population. Methods: Previously, we identified a putative CSC-like population (CD44+/CD24-) in EC cell lines and in tumor biopsy from EC patients. qPCR was used to measure the expression of mTOR in CD44+/CD24- CSC-like population of OE21 squamous cell carcinoma and OE33 adenocarcinoma cell lines compared to controls, that consisted of solid tumors generated from the same cell lines obtained from xenografts. mTOR inhibitors rapamycin and torin-1 were used to see their effect on CD44+/CD24- expression and sphere formation. Results: mTOR expression was 2-fold up-regulated in the OE33 CD44+/CD24- CSC-like population compared to control. Furthermore, in OE21 this up-regulation was 1.9-fold. Surprisingly, inhibiting the mTOR pathway with rapamycin enhanced OE33 CD44+/CD24- expression compared to its control (p = 0.01). In pilot experiments this effect was dose dependent and cells treated with rapamycin formed more spheres than control. Rapamycin did not alter the expression of CD44+/CD24- in OE21. Inhibiting the mTOR pathway with Torin-1 enhanced OE21 CD44+/CD24- expression by 1.2-fold compared to control (N = 2). In another pilot experiment Torin-1 treated cells were able to form more spheres compared to control. Torin-1 did not have an effect on the expression of CD44+/CD24- in OE33. Conclusions: These findings indicate that inhibiting the mTOR pathway may enhance CSC-like properties in EC. Additional research needs to be done to further support this hypothesis and elucidate the mechanism in this process. Furthermore, the effect of mTOR pathway inducers in EC needs to be explored.

scholarly journals mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy

2019 ◽  
Vol 20 (3) ◽  
pp. 755 ◽  
Author(s):  
Tian Tian ◽  
Xiaoyi Li ◽  
Jinhua Zhang
Keyword(s):  
Mtor Inhibitors ◽  
Genetic Alterations ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Genetic Changes ◽  
Targeting Therapy ◽  
Sequencing Technologies ◽  
Innovative Therapies ◽  
Cancer Types ◽  
New Biomarkers

The mammalian or mechanistic target of rapamycin (mTOR) pathway plays a crucial role in regulation of cell survival, metabolism, growth and protein synthesis in response to upstream signals in both normal physiological and pathological conditions, especially in cancer. Aberrant mTOR signaling resulting from genetic alterations from different levels of the signal cascade is commonly observed in various types of cancers. Upon hyperactivation, mTOR signaling promotes cell proliferation and metabolism that contribute to tumor initiation and progression. In addition, mTOR also negatively regulates autophagy via different ways. We discuss mTOR signaling and its key upstream and downstream factors, the specific genetic changes in the mTOR pathway and the inhibitors of mTOR applied as therapeutic strategies in eight solid tumors. Although monotherapy and combination therapy with mTOR inhibitors have been extensively applied in preclinical and clinical trials in various cancer types, innovative therapies with better efficacy and less drug resistance are still in great need, and new biomarkers and deep sequencing technologies will facilitate these mTOR targeting drugs benefit the cancer patients in personalized therapy.

scholarly journals Role of mTOR Signaling in Tumor Microenvironment: An Overview

2018 ◽  
Vol 19 (8) ◽  
pp. 2453 ◽  
Author(s):  
Fabiana Conciatori ◽  
Chiara Bazzichetto ◽  
Italia Falcone ◽  
Sara Pilotto ◽  
Emilio Bria ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
New Combination ◽  
Combination Therapies ◽  
Cellular Processes ◽  
Promising Target ◽  
Exogenous Cues

The mammalian target of rapamycin (mTOR) pathway regulates major processes by integrating a variety of exogenous cues, including diverse environmental inputs in the tumor microenvironment (TME). In recent years, it has been well recognized that cancer cells co-exist and co-evolve with their TME, which is often involved in drug resistance. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both the tumor immunity and angiogenesis. The activation of mTOR signaling is associated with these pro-oncogenic cellular processes, making mTOR a promising target for new combination therapies. This review highlights the role of mTOR signaling in the characterization and the activity of the TME’s elements and their implications in cancer immunotherapy.

scholarly journals mTOR Signaling in Metabolism and Cancer

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2278
Author(s):  
Shile Huang
Keyword(s):  
Physiological Activity ◽  
Mammalian Target Of Rapamycin ◽  
Hematologic Malignancies ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Promising Strategy ◽  
Different Types ◽  
And Function

The mechanistic/mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a central regulator for human physiological activity. Deregulated mTOR signaling is implicated in a variety of disorders, such as cancer, obesity, diabetes, and neurodegenerative diseases. The papers published in this special issue summarize the current understanding of the mTOR pathway and its role in the regulation of tissue regeneration, regulatory T cell differentiation and function, and different types of cancer including hematologic malignancies, skin, prostate, breast, and head and neck cancer. The findings highlight that targeting the mTOR pathway is a promising strategy to fight against certain human diseases.

Targeting mammalian target of rapamycin: prospects for the treatment of inflammatory bowel diseases

2020 ◽  
Vol 27 ◽  
Author(s):  
Naser-Aldin Lashgari ◽  
Nazanin Momeni Roudsari ◽  
Saeideh Momtaz ◽  
Negar Ghanaatian ◽  
Parichehr Kohansal ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
In Vivo Studies ◽  
Cochrane Library ◽  
Mtor Signaling Pathway ◽  
Inflammatory Bowel

: Inflammatory bowel disease (IBD) is a general term for a group of chronic and progressive disorders. Several cellular and biomolecular pathways are implicated in the pathogenesis of IBD, yet the etiology is unclear. Activation of the mammalian target of rapamycin (mTOR) pathway in the intestinal epithelial cells was also shown to induce inflammation. This review focuses on the inhibition of the mTOR signaling pathway and its potential application in treating IBD. We also provide an overview on plant-derived compounds that are beneficial for the IBD management through modulation of the mTOR pathway. Data were extracted from clinical, in vitro and in vivo studies published in English between 1995 and May 2019, which were collected from PubMed, Google Scholar, Scopus and Cochrane library databases. Results of various studies implied that inhibition of the mTOR signaling pathway downregulates the inflammatory processes and cytokines involved in IBD. In this context, a number of natural products might reverse the pathological features of the disease. Furthermore, mTOR provides a novel drug target for IBD. Comprehensive clinical studies are required to confirm the efficacy of mTOR inhibitors in treating IBD.

Targeting mTOR Signaling in Type 2 Diabetes Mellitus and Diabetes Complications

2022 ◽  
Vol 23 ◽  
Author(s):  
Lin Yang ◽  
Zhixin Zhang ◽  
Doudou Wang ◽  
Yu Jiang ◽  
Ying Liu
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Protein Complexes ◽  
Cell Metabolism ◽  
Critical Role ◽  
Mtor Inhibitors ◽  
Mtor Signaling

Abstract: The mechanistic target of rapamycin (mTOR) is a pivotal regulator of cell metabolism and growth. In the form of two different multi-protein complexes, mTORC1 and mTORC2, mTOR integrates cellular energy, nutrient and hormonal signals to regulate cellular metabolic homeostasis. In type 2 diabetes mellitus (T2DM) aberrant mTOR signaling underlies its pathological conditions and end-organ complications. Substantial evidence suggests that two mTOR-mediated signaling schemes, mTORC1-p70S6 kinase 1 (S6K1) and mTORC2-protein kinase B (AKT), play a critical role in insulin sensitivity and that their dysfunction contributes to development of T2DM. This review summaries our current understanding of the role of mTOR signaling in T2DM and its associated complications, as well as the potential use of mTOR inhibitors in treatment of T2DM.

Blocking the mTOR pathway: a drug discovery perspective

2011 ◽  
Vol 39 (2) ◽  
pp. 451-455 ◽  
Author(s):  
Carlos Garcia-Echeverria
Keyword(s):  
Drug Discovery ◽  
Cancer Patients ◽  
Cancer Biology ◽  
Human Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Mechanisms Of Action ◽  
Mtor Pathway ◽  
Lipid Kinase ◽  
Phosphoinositide 3 Kinase

Substantial drug discovery efforts have been devoted, over the last few years, to identifying and developing mTOR (mammalian target of rapamycin) kinase modulators. This has resulted in a number of mTOR inhibitors with different mechanisms of action and/or distinct protein and lipid kinase selectivity profiles. As briefly reviewed in the present paper, these compounds have provided us with a better understanding of the roles of mTOR and other phosphoinositide 3-kinase/mTOR pathway components in human cancer biology, and a few of them have already demonstrated clinical benefit in cancer patients.

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