scholarly journals Molecular Alterations of PI3K/Akt/mTOR Pathway: A Therapeutic Target in Endometrial Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Athanasia Pavlidou ◽  
Nikos F. Vlahos
Keyword(s):  
Endometrial Cancer ◽  
Mtor Inhibitors ◽  
Genetic Alterations ◽  
Mtor Pathway ◽  
Akt Pathway ◽  
Cancer Genetic ◽  
Molecular Alterations ◽  
Endometrial Cancers ◽  
Cell Growth And Proliferation ◽  
Rate Limiting

It is well established that the PI3K/Akt/mTOR pathway plays a central role in cell growth and proliferation. It has also been suggested that its deregulation is associated with cancer. Genetic alterations, involving components of this pathway, are often encountered in endometrial cancers. Understanding and identifying the rate-limiting steps of this pathway would be crucial for the development of novel therapies against endometrial cancer. This paper reviews alterations in the PI3K/Akt pathway, which could possibly contribute to the development of endometrial cancer. In addition, potential therapeutic targets of this pathway with emphasis on the mTOR inhibitors are also presented.

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 Hormone Therapy plus mTOR Inhibitors in the Treatment of Endometrial Carcinoma

2013 ◽  
Vol 09 (01) ◽  
pp. 41 ◽  
Author(s):  
Erica M Stringer ◽  
Gini F Fleming ◽  
◽  
Keyword(s):  
Endometrial Cancer ◽  
Hormonal Therapy ◽  
Single Agent ◽  
Hormonal Treatment ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Mtor Inhibition ◽  
Activating Mutations ◽  
Hormonal Therapies ◽  
Progestin Therapy

Hormonal therapies such as progestins have only modest activity in the treatment of advanced endometrial cancer. Mechanisms of resistance to progestin therapy are not well understood. However, activation of the PI3K/AKT/mTOR pathway has been associated with resistance to hormonal therapy and alterations in components of the PI3K/AKT/mTOR pathway, including inactivating mutations in PTEN, activating mutations in PIK3CA, and mutations in PIK3R1, are very common in endometrial carcinomas. mTOR inhibitors, including temsirolimus, everolimus, and ridaforolimus, are also known to be active against endometrial cancer, and interest has been stimulated in combinations of hormonal treatment with mTOR inhibitors, as both therapies have single-agent activity, and it is hypothesized that mTOR inhibition would enhance sensitivity to hormonal therapy.

The Functional Impact of PKCβ/PI3K/AKT Signalling on Translational Initiation in MCL

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2624-2624
Author(s):  
Grit Hutter ◽  
Yvonne Zimmermann ◽  
Marc Weinkauf ◽  
Alina Postnikova ◽  
Tobias Weiglein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Cell Lines ◽  
Translation Initiation ◽  
Target Genes ◽  
Mtor Inhibitors ◽  
Potential Effect ◽  
Mtor Pathway ◽  
Akt Pathway ◽  
Mtor Signalling

Abstract Introduction: Mantle cell lymphoma (MCL) is an aggressive form of B-cell non-Hodgkin’s lymphoma (NHL). It is characterized by the t(11;14)(q13;q32) translocation, which results in the overexpression of cyclinD1, a cyclin regulated by the PI3K/AKT pathway. Activation of the PI3K/AKT pathway has been shown to be involved in the pathogenesis of MCL. In addition overexpression of the protein kinase C beta (PKCβ) has been described for most cases of MCL, inhibited by enzastaurin which in turn induces apoptosis and reduces proliferation through the PKCβ/PI3K/AKT pathways. 4EBP1 is described as one of the downstream targets of PI3K/mTOR pathway linking translation initiation with PI3K/mTOR signalling as a EIF4E binding protein and playing therefore critical role in the control of protein synthesis, survival and cell growth. Targeting 4EBP1 and/or EIF4E via the PI3K/AKt/mTOR signalling or directly will affect tumor tissue. Aim of the study: The aim of the study was to determine the functional impact of PKCβ/PI3K/AKt/mTOR signaling on the translation initiation factor EIF4E, its binding protein and regulated proteins in MCL cell lines. Methods: MCL cell lines were treated with inhibitors of the PKCβ/PI3K/AKt/mTOR pathways (enzastaurin, LY294002, rapamycin) for up to 48h.The impact of the drugs on the proliferation rate of the cells was accessed after 48h by WST-assay and/or cell count. mRNA expression levels were determined using Taqmanassays. Protein phosphorylation status and protein expression were identified by westernblot. For downregulation of EIF4E in the cells sodium arsenite was used. Specific silencing of EIF4E was achieved by transfection of cells with siRNA against EIF4E. Results: The MCL celllines (5) responded to the treatment with the inhibitors of the PI3K/AKt/mTOR pathway at a IC50 for rapamycin between 5nM-50nM and for the PI3Kinhibitor between 0,31μM-5μM. Treatment of the cells with the PI3K/AKt/mTOR inhibitors induced dephosphorylation of 4EBP1 in a time-and dosedependent manner while a potential effect of the PI3K and mTOR inhibitors on the EIF4E expression and its target genes (cyclinD1, BCL2) could not be shown consistently. 4 out of 5 MCL cell lines were susceptible to enzastaurin with an IC50 between 2μM-5μM. In the not responding to enzastaurin and most resistant to rapamycin cell line (Rec-1) no 4EBP1 proteinexpression was detectable. Dephosphorylation of 4EBP1 achieved by treatment of the cells with sodium arsenit was accompanied by downregulation of EIF4E, cyclinD1 and BCL2 proteins but also stop of proliferation. The potential involvement of eIF4E gene expression in the NaAsO2-induced cytotoxicity and cell death in MCL cell lines was shown by silencing the expression of the eIF4E gene by transfection with siRNA specifically targeting the eIF4E gene expression leading to downregulation of cyclinD1, 4EBP1 proteins and cell proliferation. Conclusion: Eventhough treatment of the cells with the PI3K/AKt/mTOR inhibitors induced dephosphorylation of 4EBP1 a potential effect of the PI3K and mTOR inhibitors on the EIF4E expression and its target genes (cyclinD1, BCL2) could not be shown consistently. Instead dephosphorylation of 4EBP1 accomponied by downregulation of EIF4E or targeted downregulation of eIF4E gene expression lead to downregulation of cyclinD1 and BCL2 proteins as well as cell death in MCL. Therefore targeting the downstream targets of the PI3K/AKt/mTOR signalling 4EBP1 and/or EIF4E directly seems to be a promising anticancer strategy.

scholarly journals Hormone Therapy plus mTOR Inhibitors in the Treatment of Endometrial Carcinoma

2010 ◽  
Vol 9 (1) ◽  
pp. 18
Author(s):  
Erica M Stringer ◽  
Gini F Fleming ◽  
◽  
Keyword(s):  
Endometrial Cancer ◽  
Hormonal Therapy ◽  
Single Agent ◽  
Mammalian Target Of Rapamycin ◽  
Hormonal Treatment ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Mtor Inhibition ◽  
Hormonal Therapies ◽  
Progestin Therapy

Hormonal therapies such as progestins have only modest activity in the treatment of advanced endometrial cancer. Mechanisms of resistance to progestin therapy are not well understood. However, activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway has been associated with resistance to hormonal therapy and alterations in components of the PI3K/AKT/mTOR pathway, including inactivating mutations in PTEN, activating mutations in PIK3CA and mutations in PIK3R1, are very common in endometrial carcinomas. mTOR inhibitors, including temsirolimus, everolimus and ridaforolimus, are also known to be active against endometrial cancer, and interest has been stimulated in combinations of hormonal treatment with mTOR inhibitors, as both therapies have single-agent activity, and it is hypothesised that mTOR inhibition would enhance sensitivity to hormonal therapy.

Mutual exclusiveness between PIK3CA and KRAS mutations in endometrial carcinoma

2008 ◽  
Vol 18 (6) ◽  
pp. 1339-1343 ◽  
Author(s):  
S. Kang ◽  
S. S. Seo ◽  
H. J. Chang ◽  
C. W. Yoo ◽  
S. Y. Park ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Mutational Analysis ◽  
Statistical Significance ◽  
Single Strand Conformation Polymorphism ◽  
Genetic Alterations ◽  
Common Mutation ◽  
Kras Mutations ◽  
Endometrial Cancers ◽  
Exon 20 ◽  
Endometrial Carcinomas

In endometrial carcinomas (ECs), previous report suggested that PIK3CA mutations do not coexist with KRAS mutations, but the significant mutual exclusiveness has not been demonstrated. In this study, we examined the mutation frequency of PIK3CA in EC and its mutual exclusiveness with KRAS mutation. We performed mutational analysis of PIK3CA through a polymerase chain reaction single-strand conformation polymorphism assay in 44 cases of endometrial cancer and analyzed the correlation with loss of PTEN, KRAS mutation, and RASSF1A hypermethylation. Somatic mutations of PIK3CA were detected in 14 of 44 (31.8%) of endometrial cancers. In exon 9, seven PIK3CA mutations were located, while seven mutations were located in exon 20. The most common mutation was E545A (35.7%), followed by H1047R (28.6%). Concomitant loss of PTEN expression and PIK3CA mutation was found in four cases of endometrial cancer. KRAS mutations were mutually exclusive with PIK3CA mutations, and those mutations were inversely correlated with statistical significance (P= 0.039). Also, we found that mutations in ERBB2 were mutually exclusive with PIK3CA mutations. RASSF1A and hMLH1 methylation were not correlated with the presence of PIK3CA mutations. PIK3CA was frequently mutated in endometrial cancers. KRAS and PIK3CA mutations are inversely correlated, suggesting that genetic alterations of KRAS and PIK3CA may play equivalent roles in endometrial carcinogenesis.

scholarly journals The Search Continues: Looking for Predictive Biomarkers for Response to Mammalian Target of Rapamycin Inhibition in Endometrial Cancer

2014 ◽  
Vol 24 (4) ◽  
pp. 713-717 ◽  
Author(s):  
Larissa A. Meyer ◽  
Brian M. Slomovitz ◽  
Bojana Djordjevic ◽  
Shannon N. Westin ◽  
David A. Iglesias ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Confidence Interval ◽  
Clinical Benefit ◽  
Objective Response ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Response To Therapy ◽  
Pten Expression ◽  
Target Of Rapamycin

ObjectivePI3K/mammalian target of rapamycin (mTOR) pathway aberrations occur in 40% to 80% of endometrial cancer. Prior studies suggest KRAS mutations are associated with resistance to mTOR inhibitors in solid tumors. The objective of this study was to determine if biomarker expression in the PI3K/mTOR pathway or KRAS mutations would predict response to therapy with everolimus, an mTOR inhibitor.MethodsSpecimens from a phase II study of everolimus in recurrent endometrioid endometrial cancer were utilized. The primary end point was clinical benefit rate (CBR: objective response and nonprogression at 20 weeks). Correlative studies evaluating PTEN expression and phospho-S6 ribosomal protein (pS6rp) status by immunohistochemistry and KRAS mutational analysis were performed.ResultsSix of 28 evaluable patients achieved prolonged stable disease (SD) at 20 weeks (CBR, 21%). Loss of PTEN expression did not predict CBR (P = 0.62) with a positive predictive value (PPV) of 0.13. Five (83%) of 6 patients with SD maintained PTEN expression. Neither pS6rp expression (P = 0.65) nor KRAS mutation (P = 0.99) predicted CBR; the PPV was 0.14 for each. Eighty percent (4/5) of those with SD were KRAS wild type. Combined analysis of pS6rp expression and KRAS mutation provided 100% PPV (95% confidence interval, 39.6%–100%), suggesting no chance of CBR for these individuals with 100% specificity (95% confidence interval, 46.3%–100%).ConclusionsS6rp phosphorylation, loss of PTEN expression, and presence of KRAS mutations alone did not correlate with CBR. However, positive pS6rp staining combined with KRAS mutation performed with 100% PPV and specificity to predict nonresponse. Identifying patients who will not benefit from mTOR inhibitors can direct therapy and reduce exposure to agents that add toxicity without clinical benefit.

The Mir-17∼92 Cluster Activates mTORC1 Signaling in MCL by Targeting Multiple Regulators of the LKB1/AMPK/mTOR Pathway

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5118-5118
Author(s):  
Chengfeng Bi ◽  
Chunsun Jiang ◽  
Xiaoxing Jiang ◽  
Xin Huang ◽  
Mario R Fernandez ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Akt Pathway ◽  
Ampk Signaling ◽  
Knock Down ◽  
Protein Levels ◽  
Mtorc1 Signaling ◽  
Novel Therapeutic Strategies

Abstract Abstract 5118 Mantle cell lymphoma (MCL) is an aggressive hematological malignancy with a median survival ranging between 3 and 5 years. Novel therapeutic strategies are urgently needed to improve the outcome. Mammalian target of rapamycin (mTOR) pathway which plays a central role in controlling cell growth, proliferation and metabolism has been shown to be deregulated in MCL. mTOR inhibitors, such as rapamycin and its analogues, have been approved for treatment of relapsed/refractory MCL. However, the molecular mechanism of mTOR activation in MCL has yet to be defined. MiRNA (miR)-17∼92 is a cluster of six miRNAs which are frequently overexpressed in MCL cases and overexpression of the miR-17∼92 cluster in MCL predicts poor prognosis. Our previous study demonstrated that miR-17∼92 activated the PI3K/AKT pathway by directly targeting PTEN and PHLPP2; and knock-down of miR-17∼92 expression inhibited MCL tumor growth in a xenograft/SCID MCL mouse model. In the present study, we further demonstrated that knock-down miR-17∼92 decreased the cell size, similar effect as seen in cells treated with mTORC1 inhibitors. Knockdown of miR-17∼92 expression also decreased the glycolysis, protein synthesis and glucose uptake in MCL cells. We found that knockdown miR-17∼92 activated AMPK signaling as demonstrated by increased phosphorylation of AMPK at Thr172, especially under low glucose condition. Activated AMPK further phosphorylated TSC2 and Raptor at S1387 and S792, respectively, thereby inhibiting mTORC1 signaling as evidenced by decreased phosphorylation of RPS6 and 4E-BP1. Using TargetScan and other prediction algorithms, we found that several factors in the LKB1/AMPK/mTOR pathway, such as LKB1, CAB39, PRKAA1 and TSC1, are predicted the targets of miR-17∼92. In this study, we validated these factors as direct targets of the miR-17∼92 by 3'UTR luciferase assays using reporter plasmids containing the 3'UTR of the targets or the 3'UTR with mutations in the predicted miRNA binding sites. The protein levels of these targets decreased in MCL cells with the miR-17∼92 overexpression. Conversely, the levels of these factors were increased upon knockdown of miR-17∼92 cluster. Our results indicate that overexpression of miR-17∼92 in MCL plays important role in mTORC1 activation by inactivating the LKB1/AMPK signaling, in addition to its effect on the PI3K/AKT pathway activation. Disclosures: No relevant conflicts of interest to declare.

p53abn Endometrial Cancer: understanding the most aggressive endometrial cancers in the era of molecular classification

2021 ◽  
pp. ijgc-2020-002256
Author(s):  
Amy Jamieson ◽  
Emily F Thompson ◽  
Jutta Huvila ◽  
C Blake Gilks ◽  
Jessica N McAlpine
Keyword(s):  
Endometrial Cancer ◽  
Molecular Classification ◽  
The Cancer Genome Atlas ◽  
Small Subset ◽  
Her2 Overexpression ◽  
Lower Grade ◽  
Type I ◽  
Dna Mismatch ◽  
Molecular Alterations ◽  
Endometrial Cancers

Over the past decade, our understanding of endometrial cancer has changed dramatically from the two-tiered clinicopathologic classification system of type I and type II endometrial cancer through to the four distinct molecular subtypes identified by The Cancer Genome Atlas (TCGA) in 2013. In both systems there is a small subset of endometrial cancers (serous histotype/high numbers of somatic copy number abnormalities) that account for a disproportionately high percentage of endometrial cancer related deaths. This subset can be identified in routine clinical practice by first identifying the approximately one-third of endometrial cancers that are either ultramutated/POLEmut tumors, with pathogenic mutations in the exonuclease domain of POLE, or hypermutated/MMRd tumors, with loss of DNA mismatch repair. Immunostaining for p53 stratifies the remaining endometrial cancers into those with wild-type staining pattern and those with mutant pattern staining (p53abn endometrial cancer). This latter group of p53abn endometrial cancer is the subject of this review. Most p53abn endometrial cancers are serous type and high grade, but it also includes other histotypes and lower grade tumors, and has consistently been associated with the poorest clinical outcomes. Although it only accounts for 15% of all endometrial cancer cases, it is responsible for 50–70% of endometrial cancer mortality. A better understanding of the molecular alterations in the p53abn subgroup, beyond the ubiquitous and definitional TP53 mutations, is required so we can identify better treatments for these most aggressive endometrial cancers. Recent evidence has shown improved survival outcomes with the addition of chemotherapy compared with radiation alone in p53abn endometrial cancers. Opportunities for targeted therapy for p53abn endometrial cancers also exist with a proportion of p53abn endometrial cancers known to have homologous recombination deficiency (HRD) or human epidermal growth factor 2 (HER2) overexpression/amplification. This review will provide an overview of our current understanding of p53abn endometrial cancer.

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.

Ginkgolic acid induces apoptosis and autophagy of endometrial carcinoma cells via inhibiting PI3K/Akt/mTOR pathway in vivo and in vitro

2021 ◽  
pp. 096032712110237
Author(s):  
L Zhou ◽  
S Li ◽  
J Sun
Keyword(s):  
Endometrial Cancer ◽  
B Cells ◽  
Western Blot ◽  
Signal Pathway ◽  
Mtor Pathway ◽  
Related Protein ◽  
Western Blot Assay ◽  
Ginkgolic Acid

Endometrial cancer (EC) is the fourth most common malignancy in women in developed countries. The prognosis of EC is extremely poor, and it is an important factor that contributes to the death of patients. Therefore, studying EC pathogenesis and therapeutic targets, and exploring effective drugs are the primary tasks to improve the prognosis of EC. In the present study, we aimed to explore the function of ginkgolic acid (GA) in EC cell apoptosis and autophagy through PI3K/Akt/mTOR signal pathway in vitro and in vivo. Firstly, MTT assay and clone formation assay were employed to analyze the Ishikawa and HEC-1-B cell viabilities and proliferation after treatment with GA. The results showed that GA inhibited endometrial cancer cell survival. Flow cytometry assay and western blot assay were applied to examine the apoptosis and apoptosis related protein Bcl-2, Bax, Cleaved caspase-3 expression levels of Ishikawa and HEC-1-B cells after treatment with GA. Next, we applied western blot assay to analyze the autophagy associated proteins LC3I, LC3II, p62 and Beclin-1 in GA treated Ishikawa and HEC-1-B cells. We found that GA promoted apoptosis and induced autophagy of endometrial cancer cells. Meanwhile, western blot assay was also used to determine the expression levels of the PI3K/Akt/mTOR signal pathway related protein and the results revealed that GA inhibited the activity of PI3K/Akt/mTOR pathway. Finally, we found that GA inhibited tumor growth in vivo through immunohistochemistry assay. In conclusion, GA induces apoptosis and autophagy of EC cells via inhibiting PI3K/Akt/mTOR pathway in vivo and vitro.

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