The DOI matches its Crossref record; 239 of the 239 references it cites were found in a registry or an index.
The mTOR Signalling Pathway in Human Cancer
Open accessAbstract
The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.
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![Figure 1 Domain structure of mTOR. The N-terminus of mTOR contains two tandem repeated HEAT motifs (protein interaction domains found in Huntington, Elongation factor 3, PR65/A and TOR), followed by a FAT (domain shared by FRAP, Ataxia telangiectasia mutated, and TRRAP, all of which are PIKK family members) domain, a FRB (FKBP12-rapamycin-binding site, found in all eukaryotic TOR orthologs) domain, a PtdIns 3-kinase related catalytic domain, an auto-inhibitory (repressor domain or RD domain), and a FATC (FAT C terminus) domain that is located at the C-terminus of the protein. The FRB domain forms a deep hydrophobic cleft that serves as the high-affinity binding site for the inhibitory complex FKBP12-rapamycin (Adapted from [10]).](/paper-figures/3bfc714756d94d6aad1e028e1d0f1949/the-mtor-signalling-pathway-in-human-cancer-figure-1.jpg)
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“Although the mTOR pathway can be activated in the majority of melanomas, mTOR inhibitors have not been proven effective in this clinical setting20–22.”
From Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation (2019) · cites this paper as [20]
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Vivanco, I., & Sawyers, C. L. (2002) · Nature reviews. Cancer · doi:10.1038/nrc839 · Cited by 6,155
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Panwar, V., Singh, A., Bhatt, M., Tonk, R. K., Azizov, S., Raza, A. S., Sengupta, S., Kumar, D., & Garg, M. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01608-z · Cited by 967
The Roles of Autophagy in Cancer
Yun, C. W., & Lee, S. H. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113466 · Cited by 965
Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer
Wu, F., Yang, J., Liu, J., Wang, Y., Mu, J., Zeng, Q., Deng, S., & Zhou, H. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00641-0 · Cited by 773
Rapalogs and mTOR inhibitors as anti-aging therapeutics
Lamming, D. W., Ye, L., Sabatini, D. M., & Baur, J. A. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64099 · Cited by 531
Dysregulation of the IGF‐I/PI3K/AKT/mTOR signaling pathway in autism spectrum disorders
Chen, J., Alberts, I., & Li, X. (2014) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2014.03.006 · Cited by 151
Metadata
- Authors
- Pópulo, H., Lopes, J. M., & Soares, P.
- Affiliations
- Universidade do Porto (PT)
- Corresponding author
- Soares, Paula
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2012-02-10
- Volume
- 13
- Issue
- 2
- Pages
- 1886-1918
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC3291999
- OpenAlex
- W1965766554
- Cited by
- 830
- References
- 239
- Citations by year
- 2026: 12 · 2025: 46 · 2024: 57 · 2023: 65 · 2022: 84 · 2021: 80 · 2020: 65 · 2019: 69 · 2018: 61 · 2017: 72 · 2016: 55 · 2015: 40 · 2014: 44 · 2013: 54 · 2012: 22
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fundação para a Ciência e a Tecnologia (SFRH/BD/31369/2006)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Genetics (clinical) › Tuberous Sclerosis Complex Research
- Keywords
- mTOR signaling, mTORC1, mTORC2, PI3K/Akt signaling, rapamycin, S6K1, 4E-BP1, mRNA translation, protein kinase C alpha, actin cytoskeleton, PTEN loss, melanoma, mTOR inhibitors, temsirolimus, everolimus, renal cell carcinoma, giant cell astrocytoma, PI3K/mTOR dual inhibitor, cancer therapy
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Animals, Humans, Longevity, Melanoma, Neoplasms, Skin Neoplasms, Signal Transduction, Multiprotein Complexes, Growth and Development, TOR Serine-Threonine Kinases
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