Recent advances and limitations of mTOR inhibitors in the treatment of cancer

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Abstract

The PI3K-Akt-mechanistic (formerly mammalian) target of the rapamycin (mTOR) signaling pathway is important in a variety of biological activities, including cellular proliferation, survival, metabolism, autophagy, and immunity. Abnormal PI3K-Akt-mTOR signalling activation can promote transformation by creating a cellular environment conducive to it. Deregulation of such a system in terms of genetic mutations and amplification has been related to several human cancers. Consequently, mTOR has been recognized as a key target for the treatment of cancer, especially for treating cancers with elevated mTOR signaling due to genetic or metabolic disorders. In vitro and in vivo, rapamycin which is an immunosuppressant agent actively suppresses the activity of mTOR and reduces cancer cell growth. As a result, various sirolimus-derived compounds have now been established as therapies for cancer, and now these medications are being investigated in clinical studies. In this updated review, we discuss the usage of sirolimus-derived compounds and other drugs in several preclinical or clinical studies as well as explain some of the challenges involved in targeting mTOR for treating various human cancers.

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Hallmarks of Cancer: The Next Generation

Douglas Hanahan, Robert A. Weinberg (2011)

The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

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mTOR Signaling in Growth, Metabolism, and Disease.

Robert Saxton, David Sabatini (2017)

The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

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mTOR at the nexus of nutrition, growth, ageing and disease

Grace Y. Liu, David Sabatini (2020)

The mTOR pathway integrates a diverse set of environmental cues, such as growth factor signals and nutritional status, to direct eukaryotic cell growth. Over the past two and a half decades, mapping of the mTOR signalling landscape has revealed that mTOR controls biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Given the pathway’s central role in maintaining cellular and physiological homeostasis, dysregulation of mTOR signalling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing. In this Review, we highlight recent advances in our understanding of the complex regulation of the mTOR pathway and discuss its function in the context of physiology, human disease and pharmacological intervention.

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Author and article information

Contributors

Eunus S. Ali: eunus2ali@yahoo.com

Kangkana Mitra: kangkana.mitra.kms@gmail.com

Shamima Akter: shamima1606@gmail.com

Sarker Ramproshad: ramproshad131135@gmail.com

Banani Mondal: banani091110@gmail.com

Ishaq N. Khan: ishaqkhan.ibms@kmu.edu.pk

Muhammad Torequl Islam: mti031124@gmail.com

Javad Sharifi-Rad: javad.sharifirad@gmail.com

Daniela Calina: calinadaniela@gmail.com

William C. Cho: chocs@ha.org.hk

Journal

Journal ID (nlm-ta): Cancer Cell Int

Journal ID (iso-abbrev): Cancer Cell Int

Title: Cancer Cell International

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2867

Publication date (Electronic): 15 September 2022

Publication date PMC-release: 15 September 2022

Publication date Collection: 2022

Volume: 22

Electronic Location Identifier: 284

Affiliations

[1 ]GRID grid.1014.4, ISNI 0000 0004 0367 2697, College of Medicine and Public Health, , Flinders University, ; Bedford Park, 5042 Australia

[2 ]Gaco Pharmaceuticals, Dhaka, 1000 Bangladesh

[3 ]GRID grid.450308.a, ISNI 0000 0004 0369 268X, Faculty of Medicine and Pharmacy, , Université Grenoble Alpes, ; Grenoble, France

[4 ]GRID grid.22448.38, ISNI 0000 0004 1936 8032, Department of Bioinformatics and Computational Biology, , George Mason University, ; Fairfax, VA 22030 USA

[5 ]Department of Pharmacy, Ranada Prasad Shaha University, Narayanganj, 1400 Bangladesh

[6 ]GRID grid.444779.d, ISNI 0000 0004 0447 5097, Institute of Basic Medical Sciences, , Khyber Medical University, ; Peshawar, 25100 Pakistan

[7 ]GRID grid.449329.1, ISNI 0000 0004 4683 9733, Department of Pharmacy, Life Science Faculty, , Bangabandhu Sheikh Mujibur Rahman Science and Technology University, ; Gopalganj, 8100 Bangladesh

[8 ]GRID grid.442126.7, ISNI 0000 0001 1945 2902, Facultad de Medicina, , Universidad del Azuay, ; Cuenca, Ecuador

[9 ]GRID grid.413055.6, ISNI 0000 0004 0384 6757, Department of Clinical Pharmacy, , University of Medicine and Pharmacy of Craiova, ; 200349 Craiova, Romania

[10 ]GRID grid.415499.4, ISNI 0000 0004 1771 451X, Department of Clinical Oncology, , Queen Elizabeth Hospital, ; Kowloon, Hong Kong China

[11 ]GRID grid.16753.36, ISNI 0000 0001 2299 3507, Present Address: Department of Biochemistry and Molecular Genetics, and Simpson Querrey Institute for Epigenetics, , Northwestern University Feinberg School of Medicine, ; 303 E Superior St, Chicago, IL 60611 USA

Article

Publisher ID: 2706

DOI: 10.1186/s12935-022-02706-8

PMC ID: 9476305

PubMed ID: 36109789

SO-VID: d1884945-1d32-49a5-b70a-7b7ef5bc713d

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 30 May 2022

Date accepted : 6 September 2022

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cancer,rapamycin,mtor pathway,mtorc1,mtorc2,mtor inhibitors,targeted therapy

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cancer, rapamycin, mtor pathway, mtorc1, mtorc2, mtor inhibitors, targeted therapy

Recent advances and limitations of mTOR inhibitors in the treatment of cancer

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Karger: Oncology

Most cited references 119

Hallmarks of Cancer: The Next Generation

mTOR Signaling in Growth, Metabolism, and Disease.

mTOR at the nexus of nutrition, growth, ageing and disease

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