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Article ; Online: Mechanistic target of rapamycin inhibitors: successes and challenges as cancer therapeutics.

Bhaoighill, Muireann Ní / Dunlop, Elaine A

Cancer drug resistance (Alhambra, Calif.)

2019 Volume 2, Issue 4, Page(s) 1069–1085

Abstract: Delineating the contributions of specific cell signalling cascades to the development and maintenance of tumours has greatly informed our understanding of tumorigenesis and has advanced the modern era of targeted cancer therapy. It has been revealed that ...

Abstract	Delineating the contributions of specific cell signalling cascades to the development and maintenance of tumours has greatly informed our understanding of tumorigenesis and has advanced the modern era of targeted cancer therapy. It has been revealed that one of the key pathways regulating cell growth, the phosphatidylinositol 3-kinase/mechanistic target of rapamycin (PI3K/mTOR) signalling axis, is commonly dysregulated in cancer. With a specific, well-tolerated inhibitor of mTOR available, the impact of inhibiting this pathway at the level of mTOR has been tested clinically. This review highlights some of the promising results seen with mTOR inhibitors in the clinic and assesses some of the challenges that remain in predicting patient outcome following mTOR-targeted therapy.
Language	English
Publishing date	2019-12-19
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2578-532X
ISSN (online)	2578-532X
DOI	10.20517/cdr.2019.87
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Article ; Online: Tuberous Sclerosis Complex cell-derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers.

Bhaoighill, Muireann Ní / Falcón-Pérez, Juan M / Royo, Félix / Tee, Andrew R / Webber, Jason P / Dunlop, Elaine A

Journal of extracellular vesicles

2023 Volume 12, Issue 6, Page(s) e12336

Abstract: Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) is a feature of many solid tumours and is a key pathogenic driver in the inherited condition Tuberous Sclerosis Complex (TSC). Modulation of the tumour microenvironment by ... ...

Abstract	Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) is a feature of many solid tumours and is a key pathogenic driver in the inherited condition Tuberous Sclerosis Complex (TSC). Modulation of the tumour microenvironment by extracellular vesicles (EVs) is known to facilitate the development of various cancers. The role of EVs in modulating the tumour microenvironment and their impact on the development of TSC tumours, however, remains unclear. This study, therefore, focuses on the poorly defined contribution of EVs to tumour growth in TSC. We characterised EVs secreted from TSC2-deficient and TSC2-expressing cells and identified a distinct protein cargo in TSC2-deficient EVs, containing an enrichment of proteins thought to be involved in tumour-supporting signalling pathways. We show EVs from TSC2-deficient cells promote cell viability, proliferation and growth factor secretion from recipient fibroblasts within the tumour microenvironment. Rapalogs (mTORC1 inhibitors) are the current therapy for TSC tumours. Here, we demonstrate a previously unknown intercellular therapeutic effect of rapamycin in altering EV cargo and reducing capacity to promote cell proliferation in the tumour microenvironment. Furthermore, EV cargo proteins have the potential for clinical applications as TSC biomarkers, and we reveal three EV-associated proteins that are elevated in plasma from TSC patients compared to healthy donor plasma.
MeSH term(s)	Humans ; Tumor Suppressor Proteins ; Tuberous Sclerosis/metabolism ; Tuberous Sclerosis/pathology ; Tuberous Sclerosis Complex 2 Protein ; Extracellular Vesicles/metabolism ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Tumor Microenvironment
Chemical Substances	Tumor Suppressor Proteins ; Tuberous Sclerosis Complex 2 Protein ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
Language	English
Publishing date	2023-06-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2683797-3
ISSN	2001-3078 ; 2001-3078
ISSN (online)	2001-3078
ISSN	2001-3078
DOI	10.1002/jev2.12336
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Article ; Online: The lysosome: a crucial hub for AMPK and mTORC1 signalling.

Carroll, Bernadette / Dunlop, Elaine A

The Biochemical journal

2017 Volume 474, Issue 9, Page(s) 1453–1466

Abstract: Much attention has recently been focussed on the lysosome as a signalling hub. Following the initial discovery that localisation of the nutrient-sensitive kinase, mammalian target of rapamycin complex 1 (mTORC1), to the lysosome was essential for mTORC1 ... ...

Abstract	Much attention has recently been focussed on the lysosome as a signalling hub. Following the initial discovery that localisation of the nutrient-sensitive kinase, mammalian target of rapamycin complex 1 (mTORC1), to the lysosome was essential for mTORC1 activation, the field has rapidly expanded to reveal the role of the lysosome as a platform permitting the co-ordination of several homeostatic signalling pathways. Much is now understood about how the lysosome contributes to amino acid sensing by mTORC1, the involvement of the energy-sensing kinase, AMP-activated protein kinase (AMPK), at the lysosome and how both AMPK and mTORC1 signalling pathways feedback to lysosomal biogenesis and regeneration following autophagy. This review will cover the classical role of the lysosome in autophagy, the dynamic signalling interactions which take place on the lysosomal surface and the multiple levels of cross-talk which exist between lysosomes, AMPK and mTORC1.
MeSH term(s)	AMP-Activated Protein Kinases/metabolism ; Animals ; Autophagy/physiology ; Cell Enlargement ; Homeostasis/physiology ; Humans ; Lysosomes/metabolism ; Mechanistic Target of Rapamycin Complex 1 ; Multiprotein Complexes/metabolism ; Signal Transduction/physiology ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Multiprotein Complexes ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2017-04-13
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20160780
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Article ; Online: Tuberous sclerosis--A model for tumour growth.

Dodd, Kayleigh M / Dunlop, Elaine A

Seminars in cell & developmental biology

2016 Volume 52, Page(s) 3–11

Abstract: Tuberous sclerosis complex (TSC) is a rare genetic disorder where patients develop benign tumours in several organ systems. Central to TSC pathology is hyper-activation of the mammalian target of rapamycin complex 1 (mTORC1) signalling pathway, which is ... ...

Abstract	Tuberous sclerosis complex (TSC) is a rare genetic disorder where patients develop benign tumours in several organ systems. Central to TSC pathology is hyper-activation of the mammalian target of rapamycin complex 1 (mTORC1) signalling pathway, which is a key controller of cell growth. As a result, TSC model systems are a valuable tool for examining mTORC1-driven cellular processes. The immunosuppressant, rapamycin, is a specific inhibitor of mTORC1 and has shown promise as a therapeutic agent in TSC as well as in malignancy. This review will focus on the cellular processes controlled by mTORC1 and how TSC-deficient cell lines and mouse models have broadened our understanding of the mTORC1 signalling network. It will also discuss how our knowledge of TSC signalling can help us understand sporadic conditions where mTORC1 activity is implicated in disease onset or progression, and the possibility of using rapamycin to treat sporadic disease.
MeSH term(s)	Animals ; Autophagy ; Cell Proliferation/physiology ; Humans ; Mechanistic Target of Rapamycin Complex 1 ; Multiprotein Complexes/metabolism ; Neoplasms/genetics ; Neoplasms/pathology ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; Tuberous Sclerosis/genetics ; Tuberous Sclerosis/metabolism ; Tuberous Sclerosis/pathology
Chemical Substances	Multiprotein Complexes ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
Language	English
Publishing date	2016-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1312473-0
ISSN	1096-3634 ; 1084-9521
ISSN (online)	1096-3634
ISSN	1084-9521
DOI	10.1016/j.semcdb.2016.01.025
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Article ; Online: The kinase triad, AMPK, mTORC1 and ULK1, maintains energy and nutrient homoeostasis.

Dunlop, Elaine A / Tee, Andrew R

Biochemical Society transactions

2013 Volume 41, Issue 4, Page(s) 939–943

Abstract: In order for cells to divide in a proficient manner, they must first double their biomass, which is considered to be the main rate-limiting phase of cell proliferation. Cell growth requires an abundance of energy and biosynthetic precursors such as ... ...

Abstract	In order for cells to divide in a proficient manner, they must first double their biomass, which is considered to be the main rate-limiting phase of cell proliferation. Cell growth requires an abundance of energy and biosynthetic precursors such as lipids and amino acids. Consequently, the energy and nutrient status of the cell is acutely monitored and carefully maintained. mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] is often considered to be the master regulator of cell growth that enhances cellular biomass through up-regulation of protein translation. In order for cells to control cellular homoeostasis during growth, there is close signalling interplay between mTORC1 and two other protein kinases, AMPK (AMP-activated protein kinase) and ULK1 (Unc-51-like kinase 1). This kinase triad collectively senses the energy and nutrient status of the cell and appropriately dictates whether the cell will actively favour energy- and amino-acid-consuming anabolic processes such as cellular growth, or energy- and amino-acid-generating catabolic processes such as autophagy. The present review discusses important feedback mechanisms between these three homoeostatic protein kinases that orchestrate cell growth and autophagy, with a particular focus on the mTORC1 component raptor (regulatory associated protein of mammalian target of rapamycin), as well as the autophagy-initiating kinase ULK1.
MeSH term(s)	Adenylate Kinase/metabolism ; Autophagy ; Autophagy-Related Protein-1 Homolog ; Energy Metabolism ; Homeostasis ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Mechanistic Target of Rapamycin Complex 1 ; Multiprotein Complexes/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Multiprotein Complexes ; Autophagy-Related Protein-1 Homolog (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; ULK1 protein, human (EC 2.7.11.1) ; Adenylate Kinase (EC 2.7.4.3)
Language	English
Publishing date	2013-07-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20130030
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Zs.A 944: Show issues

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Article ; Online: Correction: Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity.

Carroll, Bernadette / Maetzel, Dorothea / Maddocks, Oliver Dk / Otten, Gisela / Ratcliff, Matthew / Smith, Graham R / Dunlop, Elaine A / Passos, João F / Davies, Owen Richard / Jaenisch, Rudolf / Tee, Andrew R / Sarkar, Sovan / Korolchuk, Viktor I

eLife

2020 Volume 9

Language	English
Publishing date	2020-12-16
Publishing country	England
Document type	Published Erratum
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.65744
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Article ; Online: Targeting protein homeostasis with nelfinavir/salinomycin dual therapy effectively induces death of mTORC1 hyperactive cells.

Dunlop, Elaine A / Johnson, Charlotte E / Wiltshire, Marie / Errington, Rachel J / Tee, Andrew R

Oncotarget

2017 Volume 8, Issue 30, Page(s) 48711–48724

Abstract: Uncontrolled cell growth in Tuberous Sclerosis Complex occurs due to inappropriate activation of mechanistic (mammalian) target of rapamycin complex 1 (mTORC1). The current therapy, rapamycin, produced promising clinical trial results, but patient ... ...

Abstract	Uncontrolled cell growth in Tuberous Sclerosis Complex occurs due to inappropriate activation of mechanistic (mammalian) target of rapamycin complex 1 (mTORC1). The current therapy, rapamycin, produced promising clinical trial results, but patient tumours regrow if treatment is discontinued, revealing rapamycin has cytostatic properties rather than a cytotoxic effect. Taking advantage of the enhanced levels of endoplasmic reticulum (ER) stress present in TSC2-null cells, we investigated drug combinations producing a cytotoxic response. We found a nelfinavir and salinomycin combination specifically killed TSC2-deficient, mTORC1 hyperactive cells. Cytotoxicity was rescued by reducing protein synthesis, either through mTORC1 inhibition or cycloheximide treatment. This indicates that the drug combination targets the cells by tipping the protein homeostasis balance of the already metabolically stressed TSC2-deficient cells in favour of cell death. Furthermore, this drug combination also inhibited tumour formation in TSC2-deficient cell models and caused tumour spheroid death in 3D culture. Importantly, the 3D assay could differentiate the cytostatic agent, rapamycin, from the cytotoxic nelfinavir/salinomycin combination. Sporadic cancer cell lines with hyperactive mTORC1 signalling were also susceptible to this nelfinavir/salinomycin drug combination. This work indicates that the protein homeostasis pathway is an attractive therapeutic target in both Tuberous Sclerosis Complex and mTORC1-driven sporadic cancers.
Language	English
Publishing date	2017-07-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.16232
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Article: Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment.

McCann, Henry D / Johnson, Charlotte E / Errington, Rachel J / Davies, D Mark / Dunlop, Elaine A / Tee, Andrew R

Cancers

2018 Volume 10, Issue 10

Abstract: To find new anti-cancer drug therapies, we wanted to exploit homeostatic vulnerabilities within Tuberous Sclerosis Complex 2 (TSC2)-deficient cells with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivity. We show that nelfinavir and ... ...

Abstract	To find new anti-cancer drug therapies, we wanted to exploit homeostatic vulnerabilities within Tuberous Sclerosis Complex 2 (TSC2)-deficient cells with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivity. We show that nelfinavir and mefloquine synergize to selectively evoke a cytotoxic response in TSC2-deficient cell lines with mTORC1 hyperactivity. We optimize the concentrations of nelfinavir and mefloquine to a clinically viable range that kill cells that lack TSC2, while wild-type cells tolerate treatment. This new clinically viable drug combination causes a significant level of cell death in TSC2-deficient tumor spheroids. Furthermore, no cell recovery was apparent after drug withdrawal, revealing potent cytotoxicity. Transcriptional profiling by RNA sequencing of drug treated TSC2-deficient cells compared to wild-type cells suggested the cytotoxic mechanism of action, involving initial ER stress and an imbalance in energy homeostatic pathways. Further characterization revealed that supplementation with methyl pyruvate alleviated energy stress and reduced the cytotoxic effect, implicating energy deprivation as the trigger of cell death. This work underpins a critical vulnerability with cancer cells with aberrant signaling through the TSC2-mTORC1 pathway that lack flexibility in homeostatic pathways, which could be exploited with combined nelfinavir and mefloquine treatment.
Language	English
Publishing date	2018-10-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers10100375
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Article ; Online: Complete loss of ATM function augments replication catastrophe induced by ATR inhibition and gemcitabine in pancreatic cancer models.

Dunlop, Charles R / Wallez, Yann / Johnson, Timothy Isaac / Bernaldo de Quirós Fernández, Sandra / Durant, Stephen T / Cadogan, Elaine B / Lau, Alan / Richards, Frances M / Jodrell, Duncan I

British journal of cancer

2020 Volume 123, Issue 9, Page(s) 1424–1436

Abstract: Background: Personalised medicine strategies may improve outcomes in pancreatic ductal adenocarcinoma (PDAC), but validation of predictive biomarkers is required. Having developed a clinical trial to assess the ATR inhibitor, AZD6738, in combination ... ...

Abstract	Background: Personalised medicine strategies may improve outcomes in pancreatic ductal adenocarcinoma (PDAC), but validation of predictive biomarkers is required. Having developed a clinical trial to assess the ATR inhibitor, AZD6738, in combination with gemcitabine (ATRi/gem), we investigated ATM loss as a predictive biomarker of response to ATRi/gem in PDAC. Methods: Through kinase inhibition, siRNA depletion and CRISPR knockout of ATM, we assessed how ATM targeting affected the sensitivity of PDAC cells to ATRi/gem. Using flow cytometry, immunofluorescence and immunoblotting, we investigated how ATRi/gem synergise in ATM-proficient and ATM-deficient cells, before assessing the impact of ATM loss on ATRi/gem sensitivity in vivo. Results: Complete loss of ATM function (through pharmacological inhibition or CRISPR knockout), but not siRNA depletion, sensitised to ATRi/gem. In ATM-deficient cells, ATRi/gem-induced replication catastrophe was augmented, while phospho-Chk2-T68 and phospho-KAP1-S824 persisted via DNA-PK activity. ATRi/gem caused growth delay in ATM-WT xenografts in NSG mice and induced regression in ATM-KO xenografts. Conclusions: ATM loss augments replication catastrophe-mediated cell death induced by ATRi/gem and may predict clinical responsiveness to this combination. ATM status should be carefully assessed in tumours from patients with PDAC, since distinction between ATM-low and ATM-null could be critical in maximising the success of clinical trials using ATM expression as a predictive biomarker.
MeSH term(s)	Animals ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors ; Ataxia Telangiectasia Mutated Proteins/genetics ; Ataxia Telangiectasia Mutated Proteins/physiology ; Carcinoma, Pancreatic Ductal/drug therapy ; Carcinoma, Pancreatic Ductal/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; Deoxycytidine/therapeutic use ; Drug Synergism ; Female ; Gene Knockout Techniques ; Humans ; Indoles ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Morpholines ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/pathology ; Pyridines/administration & dosage ; Pyridines/pharmacology ; Pyrimidines/administration & dosage ; Pyrimidines/pharmacology ; Quinolines/administration & dosage ; Quinolines/pharmacology ; RNA, Small Interfering/pharmacology ; Sulfonamides ; Sulfoxides/administration & dosage ; Sulfoxides/pharmacology ; Xenograft Model Antitumor Assays ; Gemcitabine
Chemical Substances	Indoles ; Morpholines ; Pyridines ; Pyrimidines ; Quinolines ; RNA, Small Interfering ; Sulfonamides ; Sulfoxides ; Deoxycytidine (0W860991D6) ; ceralasertib (85RE35306Z) ; ATM protein, human (EC 2.7.11.1) ; ATR protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; AZD0156 (P5T0XWC07Z) ; Gemcitabine
Language	English
Publishing date	2020-08-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-020-1016-2
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Article ; Online: Correction

Bernadette Carroll / Dorothea Maetzel / Oliver DK Maddocks / Gisela Otten / Matthew Ratcliff / Graham R Smith / Elaine A Dunlop / João F Passos / Owen Richard Davies / Rudolf Jaenisch / Andrew R Tee / Sovan Sarkar / Viktor I Korolchuk

eLife, Vol

Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity

2020 Volume 9

Keywords	Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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