The PI3K/Akt/mTOR pathway: A potential pharmacological target in COVID-19.
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ABSTRACT:
SUBMITTER: Basile MS
PROVIDER: S-EPMC8574122 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Coronavirus disease 2019 (COVID-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A single-stranded RNA virus from a β-Coronaviridae family causes acute clinical manifestations. Its high death rate and severe clinical symptoms have turned it into the most significant challenge worldwide. Up until now, several effective COVID-19 vaccines have been designed and marketed, but our data on specialized therapeutic drugs for the treatment of COVID-19 is still limited. In order to synthesis virus particles, SARS-CoV-2 uses host metabolic pathways such as phosphoinositide3-kinase (PI3K)/protein kinase B (PKB, also known as AKT)/mammalian target of rapamycin (mTOR). mTOR is involved in multiple biological processes. Over-activation of the mTOR pathway improves viral replication, which makes it a possible target in COVID-19 therapy. Clinical data shows the hyperactivation of the mTOR pathway in lung tissues during respiratory viral infections. However, the exact impact of mTOR pathway inhibitors on the COVID-19 severity and death rate is yet to be thoroughly investigated. There are several mTOR pathway inhibitors. Rapamycin is the most famous inhibitor of mTORC1 among all. Studies on other respiratory viruses suggest that the therapeutic inhibitors of the mTOR pathway, especially rapamycin, can be a potential approach to anti-SARS-CoV-2 therapy. Using therapeutic methods that inhibit harmful immune responses can open a new chapter in treating severe COVID-19 disease. We highlighted the potential contribution of PI3K/Akt/mTOR inhibitors in the treatment of COVID-19.
| S-EPMC8808470 | biostudies-literature
Project description:In the last decade, pathway-specific targeted therapy has revolutionized colorectal cancer (CRC) treatment strategies. This type of therapy targets a tumor-vulnerable spot formed primarily due to an alteration in an oncogene and/or a tumor suppressor gene. However, tumor heterogeneity in CRC frequently results in treatment resistance, underscoring the need to understand the molecular mechanisms involved in CRC for the development of novel targeted therapies. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/Akt/mTOR) signaling pathway axis is a major pathway altered in CRC. The aberrant activation of this pathway is associated with CRC initiation, progression, and metastasis and is critical for the development of drug resistance in CRC. Several drugs target PI3K/Akt/mTOR in clinical trials, alone or in combination, for the treatment of CRC. This review aims to provide an overview of the role of the PI3K/Akt/mTOR signaling pathway axis in driving CRC, existing PI3K/Akt/mTOR-targeted agents against CRC, their limitations, and future trends.
| S-EPMC10970097 | biostudies-literature
Project description:The PI3K/AKT/mTOR pathway is commonly activated in non-small-cell lung cancer. It plays important roles in promoting oncogenesis in lung cancer and mediating resistance to EGF receptor tyrosine kinase inhibitors. Targeted agents against the components of this pathway are currently in development and their clinical benefits remain to be defined. This review provides an overview of the pathway dysregulation and novel agents targeting the pathway in lung cancer. In addition, potential predictive biomarkers guiding patient selection for targeted PI3K/AKT/mTOR inhibition is also discussed.
| S-EPMC4203662 | biostudies-literature
Project description:Chordomas are radio- and chemo-resistant tumours and metastasise in as many as 40% of patients. The aim of this study was to identify potential molecular targets for the treatment of chordoma. In view of the reported association of chordoma and tuberous sclerosis complex syndrome, and the available therapeutic agents against molecules in the PI3K/AKT/TSC1/TSC2/mTOR pathway, a tissue microarray of 50 chordoma cases was analysed for expression of active molecules involved in this signalling pathway by immunohistochemistry and a selected number by western blot analysis. Chordomas were positive for p-AKT (92%), p-TSC2 (96%), p-mTOR (27%), total mTOR (75%), p-p70S6K (62%), p-RPS6 (22%), p-4E-BP1 (96%) and eIF-4E (98%). Phosphatase and tensin homologue deleted on chromosome 10 expression was lost in 16% of cases. Mutations failed to be identified in PI3KCA and RHEB1 in the 23 cases for which genomic DNA was available. Fluorescence in situ hybridisation analysis for mTOR and RPS6 loci showed that 11 of 33 and 21 of 44 tumours had loss of one copy of the respective genes, results which correlated with the loss of the relevant total proteins. Fluorescence in situ hybridisation analysis for loci containing TSC1 and TSC2 revealed that all cases analysed harboured two copies of the respective genes. On the basis of p-mTOR and or p-p70S6K expression there is evidence indicating that 65% of the chordomas studied may be responsive to mTOR inhibitors, rapamycin or its analogues, and that patients may benefit from combined therapy including drugs that inhibit AKT.
| S-EPMC2694420 | biostudies-literature
Project description: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.
| S-EPMC3913524 | biostudies-literature
Project description:BackgroundBrain metastases (BM) are a frequent complication of malignant melanoma (MM), with limited treatment options and poor survival. Prevention of BM could be more effective and better tolerated than treating established BM in various conditions.MethodsTo investigate the temporospatial dynamics of PI3K/Akt/mTOR (PAM) pathway activation during BM formation and the preventive potential of its inhibition, in vivo molecular imaging with an Akt biosensor was performed, and long-term intravital multiphoton microscopy through a chronic cranial window in mice.ResultsIn vivo molecular imaging revealed invariable PAM pathway activation during the earliest steps of brain colonization. In order to perform a long-term intravascular arrest and to extravasate, circulating MM cells needed to activate their PAM pathway during this process. However, the PAM pathway was quite heterogeneously activated in established human brain metastases, and its inhibition with the brain-penetrant PAM inhibitor GNE-317 resulted in only modest therapeutic effects in mice. In contrast, giving GNE-317 in preventive schedules that included very low doses effectively reduced the growth rate and number of BM in two MM mouse models over time, and led to an overall survival benefit. Longitudinal intravital multiphoton microscopy found that the first, rate-limiting steps of BM formation-permanent intravascular arrest, extravasation, and initial perivascular growth-are most vulnerable to dual PI3K/mTOR inhibition.ConclusionThese findings establish a key role of PAM pathway activation for critical steps of early metastatic brain colonization and reveal its pharmacological inhibition as a potent avenue to prevent the formation of clinically relevant BM.
| S-EPMC8804893 | biostudies-literature
Project description:The present study examined the expression of mammalian target of rapamycin (mTOR) and mutations in the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway in 54 patients with typical carcinoid tumours (TC) or atypical carcinoid tumours (AC). In total, 54 bronchopulmonary neuroendocrine tumour (NET) surgical specimens, consisting of 17 TC, 8 AC, 17 large-cell neuroendocrine carcinoma (LCNEC), and 12 small-cell lung carcinoma (SCLC) samples, were tested for mTOR by immunohistochemistry, and 104 exon sites were tested in the PI3K/AKT/mTOR pathway by nested polymerase chain reaction. It was found that the positive rates for mTOR expression in TC/AC and LCNEC/SCLC were 60 (15/25) and 55.2% (16/29), respectively. In total, 4 missense mutations were found in 3 patients with TC/AC, including mutations in exon 48 of mTOR (c.6667C>T), exon 21 of tuberous sclerosis complex (TSC) 1 (c.2765G>A), and exons 12 (c.1265C>T) and 19 (c.2148C>T) of TSC2. To the best of our knowledge, mutations in exon 48 of mTOR and exon 21 of TSC1 have not been previously reported. Tissues from patients with single mutations exhibited strong positive mTOR immunohistochemical staining, and tissues from patients with double mutations were weakly positive. The same mutations were not observed in SCLC or LCNEC. In conclusion, gene mutations were observed and an association between the gene mutations and mTOR expression were indicated in the PI3K/AKT/mTOR pathway in TC/AC tumours. Those mutations may be driver genes and treatment targets.
| S-EPMC5529984 | biostudies-other
Project description:It is well established that the PI3K pathway plays a central role in various cellular processes that can contribute to the malignant phenotype. Accordingly, pharmacological inhibition of key nodes in this signaling cascade has been a focus in developmental therapeutics. To date, agents targeting upstream receptor tyrosine kinases are best studied and have achieved greatest clinical success. Further downstream, despite efficacy in certain tumor types, the rapalogs have been somewhat disappointing in the clinic. Novel inhibitors of PI3K, Akt, and mTORC1 and 2 are now passing through early phase clinical trials. It is hoped that these agents will circumvent some of the shortcomings of the rapalogs and lead to meaningful benefits for cancer patients.
| S-EPMC3248125 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against KRAS, a mutation present in an overwhelming majority of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provides promising therapeutic targets in the management of PDAC and warrants further exploration. Here, we investigated Urolithin A (Uro A), a novel natural compound derived from pomegranates, which targets numerous kinases downstream of KRAS, in particular the PI3K/AKT/mTOR signaling pathways. We showed that treatment of PDAC cells with Uro A blocked the phosphorylation of AKT and p70S6K in vitro, successfully inhibited the growth of tumor xenografts, and increased overall survival of Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice compared with vehicle or gemcitabine therapy alone. Histologic evaluation of these Uro A-treated tumor samples confirmed mechanistic actions of Uro A via decreased phosphorylation of AKT and p70S6K, reduced proliferation, and increased cellular apoptosis in both xenograft and PKT mouse models. In addition, Uro A treatment reprogrammed the tumor microenvironment, as evidenced by reduced levels of infiltrating immunosuppressive cell populations such as myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Overall, this work provides convincing preclinical evidence for the utility of Uro A as a therapeutic agent in PDAC through suppression of the PI3K/AKT/mTOR pathway.
| S-EPMC6363854 | biostudies-literature
Project description:Gastrointestinal stromal tumor (GIST) originates from interstitial cells of Cajal (ICCs) in the myenteric plexus of the gastrointestinal tract. Most GISTs arise due to mutations of KIT and PDGFRA gene activation, encoding the receptor tyrosine kinase (RTK). The clinical use of the RTK inhibitor imatinib has significantly improved the management of GIST patients; however, imatinib resistance remains a challenge. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a critical survival pathway for cell proliferation, apoptosis, autophagy and translation in neoplasms. Constitutive autophosphorylation of RTKs has an impact on the activation of the PI3K/AKT/mTOR pathway. In several preclinical and early-stage clinical trials PI3K/AKT/mTOR signaling inhibition has been considered as a promising targeted therapy strategy for GISTs. Various inhibitory drugs targeting different parts of the PI3K/AKT/mTOR pathway are currently being investigated in phase I and phase II clinical trials. This review highlights the progress for PI3K/AKT/mTOR-dependent mechanisms in GISTs, and explores the relationship between mTOR downstream signals, in particular, eukaryotic initiation factors (eIFs) and the development of GISTs, which may be instrumental for identifying novel therapeutic targets.
| S-EPMC7602170 | biostudies-literature