scholarly journals BET protein inhibition evidently enhances sensitivity to PI3K/mTOR dual inhibition in intrahepatic cholangiocarcinoma

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Xiaolong Miao ◽  
Chen Liu ◽  
Yuancong Jiang ◽  
Yao Wang ◽  
Deqiang Kong ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Intrahepatic Cholangiocarcinoma ◽  
Molecular Targeted Therapy ◽  
Antitumour Activity ◽  
Primary Liver Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Dual Inhibitor

AbstractIntrahepatic cholangiocarcinoma (ICC), the second most common primary liver cancer, is a fatal malignancy with a poor prognosis and only very limited therapeutic options. Although molecular targeted therapy is emerged as a promising treatment strategy, resistance to molecular-targeted therapy occurs inevitably, which represents a major clinical challenge. In this study, we confirmed that mammalian target of rapamycin (mTOR) signaling is the most significantly affected pathways in ICC. As a novel phosphoinositide 3-kinase (PI3K)/mTOR dual inhibitor, BEZ235, exerts antitumour activity by effectively and specifically blocking the dysfunctional activation of the PI3K/serine/threonine kinase (AKT)/mTOR pathway. We generate the orthotopic ICC mouse model through hydrodynamic transfection of AKT and yes-associated protein (YAP) plasmids into the mouse liver. Our study confirmed that BEZ235 can suppress the proliferation, invasion and colony conformation abilities of ICC cells in vitro but cannot effectively inhibit ICC progression in vivo. Inhibition of PI3K/mTOR allowed upregulation of c-Myc and YAP through suppressed the phosphorylation of LATS1. It would be a novel mechanism that mediated resistance to PI3K/mTOR dual inhibitor. However, Bromo- and extraterminal domain (BET) inhibition by JQ1 downregulates c-Myc and YAP transcription, which could enhance the efficacy of PI3K/mTOR inhibitors. The efficacy results of combination therapy exhibited effective treatment on ICC in vitro and in vivo. Our data further confirmed that the combination of PI3K/mTOR dual inhibitor and BET inhibition induces M1 polarization and suppresses M2 polarization in macrophages by regulating the expression of HIF-1α. Our study provides a novel and efficient therapeutic strategy in treating primary ICC.

scholarly journals BET Protein Inhibition Evidently Enhances Sensitivity to PI3K/mTOR Dual Inhibition in Intrahepatic Cholangiocarcinoma

2021 ◽  
Author(s):  
Xiaolong Miao ◽  
Weihua Gong
Keyword(s):  
Targeted Therapy ◽  
Combination Therapy ◽  
Intrahepatic Cholangiocarcinoma ◽  
Molecular Targeted Therapy ◽  
Primary Liver Cancer ◽  
Mtor Inhibitors ◽  
Dual Inhibitor ◽  
Hydrodynamic Transfection

Abstract Background & Aims: Intrahepatic cholangiocarcinoma (ICC), the second most common primary liver cancer, is a fatal malignancy with a poor prognosis. Molecular targeted therapy is a promising treatment strategy. However, resistance to molecular-targeted therapy is inevitable and represents a major clinical challenge. Our objective was to provide a novel and efficient therapeutic strategy in treating primary ICC.Approach & Results: We generated an orthotopic ICC mouse model through hydrodynamic transfection of AKT and YAP into mouse liver. Genetic approaches were applied to study the mechanism that mediated resistance to a PI3K/mTOR dual inhibitor in mediating AKT/YapS127A-driven tumorigenesis. Haematoxylin and eosin staining, immunohistochemistry and immunoblotting were applied to assess the efficacy of ICC combination therapy in vitro and in vivo.Conclusions: We confirmed that mTOR signalling is the most significantly affected pathway in ICC. BEZ235, a novel PI3K/mTOR dual inhibitor, can suppress the proliferation, invasion and colony formation abilities of ICC cells in vitro but cannot effectively inhibit ICC progression in vivo. The inhibition of PI3K/mTOR allowed the upregulation of c-Myc and YAP through the suppression of the phosphorylation of LATS1. This is a novel mechanism that mediates resistance to PI3K/mTOR dual inhibitors. However, BET inhibition by JQ1 downregulates c-Myc and YAP transcription, which could enhance the efficacy of PI3K/mTOR inhibitors. The efficacy results of combination therapy exhibited effective treatment of ICC in vitro and in vivo. Our data further confirmed that the combination of a PI3K/mTOR dual inhibitor and BET inhibition induces M1 polarization and suppresses M2 polarization in macrophages by regulating the expression of HIF-1a.

scholarly journals SPDR-1 HSP90 inhibition overcomes resistant to molecular targeted therapy in BRAFV600E mutant glioblastoma

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi3-vi3
Author(s):  
Jo Sasame ◽  
Naoki Ikegaya ◽  
Yohei Miyake ◽  
Takahiro Hayashi ◽  
Akito Oshima ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Molecular Targeted Therapy ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Mtor Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Hsp90 Inhibition ◽  
Pdx Models

Abstract The BRAFV600E mutation results in the constitutive activation of downstream mitogen activated protein kinase (MAPK) pathway that promotes tumor growth. Recently, molecular targeted therapy using BRAF/MEK inhibitor has been reported for BRAFV600E mutant high-grade glioma, but the therapeutic effect is limited by the emergence of drug resistance. Herein, we established paired BRAFV600E mutant glioblastoma (GBM) patient-derived xenograft (PDX) models, which were derived from tumors at prior to and recurrence after molecular targeted therapy. These PDX models were found to extensively recapitulate the histology, genetic abnormalities, and even the clinical course of the patients. Furthermore, BRAF/MEK inhibitor gradually caused resistance in cell lines derived from specimens that initially responded to molecular targeted therapy. In this study, genomic and epigenomic changes had little effect on the resistance mechanism. On the other hand, we found that hyperactivation of the MAPK pathway through c-Raf and the AKT/mTOR pathway primarily caused resistance to molecular targeted therapy in BRAFV600E mutant GBM. Through a high throughput drug screening, we find that HSP90 inhibitor with BRAF/MEK inhibitor coordinately deactivates MAPK pathway and AKT/mTOR pathway, and mediates potent toxicity in vitro and in vivo in refractory and acquired resistant models. These findings support that this therapeutic approach can overcome the limitation of current molecular targeted therapy in BRAFV600E mutant GBM.

scholarly journals PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1902 ◽  
Author(s):  
Gabriel Mpilla ◽  
Amro Aboukameel ◽  
Irfana Muqbil ◽  
Steve Kim ◽  
Rafic Beydoun ◽  
...  
Keyword(s):  
Cell Lines ◽  
Neuroendocrine Tumors ◽  
Clinical Investigation ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Residual Tumor ◽  
Pancreatic Neuroendocrine Tumors ◽  
Nicotinamide Phosphoribosyltransferase

Pancreatic neuroendocrine tumors (PNET) remain an unmet clinical need. In this study, we show that targeting both nicotinamide phosphoribosyltransferase (NAMPT) and p21-activated kinase 4 (PAK4) could become a synthetic lethal strategy for PNET. The expression of PAK4 and NAMPT was found to be higher in PNET tissue compared to normal cells. PAK4-NAMPT dual RNAi suppressed proliferation of PNET cell lines. Treatment with KPT-9274 (currently in a Phase I trial or analogs, PF3758309 (the PAK4 selective inhibitor) or FK866 (the NAMPT inhibitor)) suppressed the growth of PNET cell lines and synergized with the mammalian target of rapamycin (mTOR) inhibitors everolimus and INK-128. Molecular analysis of the combination treatment showed down-regulation of known everolimus resistance drivers. KPT-9274 suppressed NAD pool and ATP levels in PNET cell lines. Metabolomic profiling showed a statistically significant alteration in cellular energetic pathways. KPT-9274 given orally at 150 mg/kg 5 days/week for 4 weeks dramatically reduced PNET sub-cutaneous tumor growth. Residual tumor analysis demonstrated target engagement in vivo and recapitulated in vitro results. Our investigations demonstrate that PAK4 and NAMPT are two viable therapeutic targets in the difficult to treat PNET that warrant further clinical investigation.

scholarly journals Noncanonical TGF-β pathways, mTORC1 and Abl, in renal interstitial fibrogenesis

2010 ◽  
Vol 298 (1) ◽  
pp. F142-F149 ◽  
Author(s):  
Shinong Wang ◽  
Mark C. Wilkes ◽  
Edward B. Leof ◽  
Raimund Hirschberg
Keyword(s):  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Transforming Growth Factor Β ◽  
Renal Diseases ◽  
Obstructive Nephropathy ◽  
Renal Fibrogenesis

Renal interstitial fibrosis is a major determinant of renal failure in the majority of chronic renal diseases. Transforming growth factor-β (TGF-β) is the single most important cytokine promoting renal fibrogenesis. Recent in vitro studies identified novel non-smad TGF-β targets including p21-activated kinase-2 (PAK2), the abelson nonreceptor tyrosine kinase (c-Abl), and the mammalian target of rapamycin (mTOR) that are activated by TGF-β in mesenchymal cells, specifically in fibroblasts but less in epithelial cells. In the present studies, we show that non-smad effectors of TGF-β including PAK2, c-Abl, Akt, tuberin (TSC2), and mTOR are activated in experimental unilateral obstructive nephropathy in rats. Treatment with c-Abl or mTOR inhibitors, imatinib mesylate and rapamycin, respectively, each blocks noncanonical (non-smad) TGF-β pathways in the kidney in vivo and diminishes the number of interstitial fibroblasts and myofibroblasts as well as the interstitial accumulation of extracellular matrix proteins. These findings indicate that noncanonical TGF-β pathways are activated during the early and rapid renal fibrogenesis of obstructive nephropathy. Moreover, the current findings suggest that combined inhibition of key regulators of these non-smad TGF-β pathways even in dose-sparing protocols are effective treatments in renal fibrogenesis.

scholarly journals mTOR Pathway and mTOR Inhibitors in Head and Neck Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Wei Gao ◽  
John Zeng Hong Li ◽  
Jimmy Yu Wai Chan ◽  
Wai Kuen Ho ◽  
Thian-Sze Wong
Keyword(s):  
Head And Neck Cancer ◽  
Targeted Therapy ◽  
Head And Neck ◽  
Neck Cancer ◽  
Xenograft Model ◽  
Mtor Inhibitors ◽  
Chemotherapeutic Agents ◽  
Therapeutic Effects

Head and neck cancer is the sixth most common type of Cancer worldwide. Since conventional treatment regimens are nonselective and are associated with systemic toxicities, intense investigations focus on molecular targeted therapy with high selectivity and low adverse effects. mTOR signaling pathway has been found to be activated in head and neck cancer, making it attractive for targeted therapy. In addition, expression levels of mTOR and downstream targets eIF4E, 4EBP1, S6K1, and S6 are potential diagnostic and prognostic biomarkers for head and neck cancer. mTOR inhibitors, such as rapamycin and its derivatives temsirolimus and everolimus, exhibit inhibitory effects on head and neck cancer in both in vitro cell line model and in vivo xenograft model. A large number of clinical trials have been initiated to evaluate the therapeutic effects of mTOR inhibitors on patients with head and neck cancer. mTOR inhibitor has potential as a single therapeutic agent or in combination with radiation, chemotherapeutic agents, or other targeted therapeutic agents to obtain synergistic repression on head and neck cancer.

scholarly journals Targeting the PI3K/AKT/mTOR Signaling Pathway in Lung Cancer: An Update Regarding Potential Drugs and Natural Products

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 4100
Author(s):  
Iksen ◽  
Sutthaorn Pothongsrisit ◽  
Varisa Pongrakhananon
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Signaling Pathway ◽  
Therapeutic Potential ◽  
Mammalian Target Of Rapamycin ◽  
Tumor Development ◽  
Mtor Inhibitors ◽  
Mtor Signaling

Lung cancer is one of the most common cancers and has a high mortality rate. Due to its high incidence, the clinical management of the disease remains a major challenge. Several reports have documented a relationship between the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and lung cancer. The recognition of this pathway as a notable therapeutic target in lung cancer is mainly due to its central involvement in the initiation and progression of the disease. Interest in using natural and synthetic medications to target these signaling pathways has increased in recent years, with promising results in vitro, in vivo, and in clinical trials. In this review, we focus on the current understanding of PI3K/AKT/mTOR signaling in tumor development. In addition to the signaling pathway, we highlighted the therapeutic potential of recently developed PI3K/AKT/mTOR inhibitors based on preclinical and clinical trials.

Anti-Angiongenic Effects of mTOR-Inhibitors Is Regulated by AKT Activity in Multiple Myeloma Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3406-3406
Author(s):  
Patrick Frost ◽  
Bao Hoang ◽  
Yijiang Shi ◽  
Huajun Yan ◽  
Alan Lichtenstein
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Apoptotic Cell ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Mtor Inhibitors ◽  
Underlying Mechanisms ◽  
Salvage Pathways

Abstract Inhibitors of the mammalian target of rapamycin (mTOR), such as rapamycin (RAPA) and CCI-779 (CCI), have potential as anti-tumor agents against multiple myeloma (MM). Since other tumor models have demonstrated that heightened AKT activity induces hypersensitivity to mTOR inhibitors, we stably transfected U266 human MM cells with a constitutively activated AKT allele (U266-AKT) or empty vector control (U266-EV) in order to further explore the underlying mechanisms of this phenomena. Analysis of cell death demonstrated that U266-AKT were significantly more sensitive to RAPA in vitro, with an ED50 of 0.01 nM versus an ED50 of >100 nM for U266-EV control cells. A similar alteration of sensitivity to CCI was demonstrated in U266 isogenic tumors grown in NOD/SCID mice and treated with CCI in vivo. Analysis of the excised tumor nodules demonstrated a >5 fold inclease in apoptotic nuclei in U266-AKT tumors treated with CCI compared to isogenic control tumors, despite previous reports that mTOR inhibitors do not induce apoptosis in MM cells in vitro. One potential explanation for this is that AKT regulates the ability of CCI to inhibit angiogenesis, which is only relevent in vivo, and thereby indirectly induces apoptotic cell death. In support of this hypothesis, we demonstrated that CCI significantly decreased angiogenesis (measued by in situ staining of excised tumor nodules with CD34, a marker for endothelial cells) by 80% in U266-AKT, and only by 67% in isogenic controls. Since previous studies demonstrated that AKT/mTOR regulates the expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1a (HIF1a), we hypothesized that MM cells with heightened AKT activity may be more sensitive to the CCI-mediated inhibition of these critical angiogenic factors. In vitro, RAPA was markedly more effective at inhibiting HIF-1a and VEGF expression from U266-AKT compared to U266-EV control cells. One possible explanation for the regulatory role of AKT in the RAPA/CCI response is that MM cells with hyperactive AKT function depend upon mTOR-mediated (i.e. cap-dependent) translational pathway to express critical proteins like VEGF and HIF-1a, while “low-AKT” MM cells may be able to utilize non-mTOR dependent (i.e. cap-independent) salvage pathways to express these critical proteins and are thereby resistant to mTOR inhibitors.

Mammalian target of rapamycin (mTOR) pathway signalling in lymphomas

2008 ◽  
Vol 10 ◽  
Author(s):  
Elias Drakos ◽  
George Z. Rassidakis ◽  
L. Jeffrey Medeiros
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Central Element ◽  
Mtor Inhibitors ◽  
Chemotherapeutic Agents ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
In Vivo Studies ◽  
Mtor Inhibition

AbstractThe mammalian target of rapamycin mTOR is a central element in an evolutionary conserved signalling pathway that regulates cell growth, survival and proliferation, orchestrating signals originating from growth factors, nutrients or particular stress stimuli. Two important modulators of mTOR activity are the AKT and ERK/MAPK signalling pathways. Many studies have shown that mTOR plays an important role in the biology of malignant cells, including deregulation of the cell cycle, inactivation of apoptotic machinery and resistance to chemotherapeutic agents. The development of several mTOR inhibitors, in addition to rapamycin, has facilitated studies of the role of mTOR in cancer, and verified the antitumour effect of mTOR inhibition in many types of neoplasms, including lymphomas. Clinical trials of rapamycin derivatives in lymphoma patients are already in development and there are encouraging preliminary results, such as the substantial response of a subset of mantle cell lymphoma patients to the rapamycin analogue temsirolimus. Based on results obtained from in vitro and in vivo studies of the mTOR pathway in lymphomas, it seems that better understanding of mTOR regulation will reveal aspects of lymphomagenesis and contribute to the development of more powerful, targeted therapies for lymphoma patients.

scholarly journals Lenvatinib Inhibits Intrahepatic Cholangiocarcinoma Growth via Gadd45a-Mediated Cell Cycle Arrest

2021 ◽  
Author(s):  
Xia Yan ◽  
Dan Wang ◽  
Liping Zhuang ◽  
Peng Wang ◽  
Zhiqiang Meng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Intrahepatic Cholangiocarcinoma ◽  
Primary Liver Cancer ◽  
Transcriptional Profiling ◽  
Cycle Arrest

Abstract Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer, and its 5-year survival rate is less than 10%. Fibroblast growth factor receptor (FGFR) changes have been observed in 6%-50% of ICC patients, and patients with FGFR mutations have been shown to have more inert tumour biological activity than patients with wild-type FGFRs. Thus, as a pan-FGFR inhibitor, lenvatinib is supposed to play an anti-tumour role in ICC. However, no relevant experiments have been reported.Methods: Patients derived xenograft (PDX) model and cell line derived xenograft (CDX) model were both used for the in vivo study. For in vivo work, ICC cell lines were applied to analyse the effect of Lenvatinib on cell proliferation, cell cycle progression, apoptosis, and the molecular mechanism.Reaults: In the present study, we found that lenvatinib dramatically hindered in vivo tumor growth in ICC patient-derived xenograft models. In addition, by using in vitro experiments in ICC cell lines, we found that lenvatinib dose- and time-dependently inhibited the proliferation of ICC cells and induced cell cycle arrest in the G0/G1 phase. Transcriptional profiling analysis further applied indicated that lenvatinib might inhibit cell proliferation through the induction of cell-cycle arrestment via activating of Gadd45a, it was evidenced by that the knockout of Gadd45a significantly attenuated the cycle arrest induced by lenvatinib, as well as the inhibitory effect of lenvatinib on ICC.Conclusion: Our work firstly found that lenvatinib exerted excellent antitumor effect on ICC, mainly via inducing Gadd45a mediated cell cycle arrest. Our work provides evidence and a rationale for the future use of lenvatinib in the treatment of ICC.

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