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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Items 201–239 of 239
Coleman, L., Peter, M. B., Teall, T. J., et al. (2009) · British Journal of Cancer · doi:10.1038/sj.bjc.6605044 · Cited by 112
Overcoming apoptosis deficiency of melanoma—Hope for new therapeutic approaches
Eberle, J., Kurbanov, B. M., Hossini, A. M., Trefzer, U., & Fecker, L. F. (2007) · Drug Resistance Updates · doi:10.1016/j.drup.2007.09.001 · Cited by 112
Molhoek, K. R., Brautigan, D. L., & Slingluff, C. L. (2005) · Journal of Translational Medicine · doi:10.1186/1479-5876-3-39 · Cited by 112
The FKBP12‐rapamycin‐associated protein (FRAP) is a CLIP‐170 kinase
Choi, J. H., Bertram, P. G., Drenan, R. M., Carvalho, J. J., Zhou, H. H., & Zheng, X.-F. (2002) · EMBO Reports · doi:10.1093/embo-reports/kvf197 · Cited by 98
Takahashi, K., Nakagawa, M., Young, S. G., & Yamanaka, S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506280200 · Cited by 97
Smalley, K. S. M., & Eisen, T. G. (2003) · International Journal of Cancer · doi:10.1002/ijc.11064 · Cited by 96
Lu, Z. H., Shvartsman, M. B., Lee, A. Y., Shao, J. M., Murray, M. M., Kladney, R. D., Fan, D., Krajewski, S., Chiang, G. G., Mills, G. B., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3467 · Cited by 94
Ogawa, T., Tokuda, M., Tomizawa, K., Matsui, H., Itano, T., Konishi, R., Nagahata, S., & Hatase, O. (1998) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1998.9118 · Cited by 92
Kristof, A. S., Marks-Kończalik, J., Billings, E. M., & Moss, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301053200 · Cited by 92
Identification of PTEN mutations in metastatic melanoma specimens
Çelebi, J. T., Shendrik, I., Silvers, D. N., & Peacocke, M. (2000) · Journal of Medical Genetics · doi:10.1136/jmg.37.9.653 · Cited by 90
Signalling by CD95 and TNF receptors: Not only life and death
Magnusson, C., & Vaux, D. L. (1999) · Immunology and Cell Biology · doi:10.1046/j.1440-1711.1999.00800.x · Cited by 82
Evaluation of the mTOR pathway in ocular (uvea and conjunctiva) melanoma
Pópulo, H., Soares, P., Rocha, A. S., Silva, P., & Lopes, J. M. (2010) · Melanoma Research · doi:10.1097/cmr.0b013e32832ccd09 · Cited by 79
Self-citationHsp70 associates with Rictor and is required for mTORC2 formation and activity
Martin, J., Masri, J., Bernath, A., Nishimura, R. N., & Gera, J. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.05.086 · Cited by 79
REIFENBERGER, J., Wolter, M., Bostr�m, J., B�schges, R., Megahed, M., Ruzicka, T., Schulte, K. W., & Reifenberger, G. (2000) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s004280050477 · Cited by 79
Dan, H. C., & Baldwin, A. S. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.11.7582 · Cited by 76
Noh, W. C., Kim, Y. H., Kim, M. S., et al. (2007) · Breast Cancer Research and Treatment · doi:10.1007/s10549-007-9746-x · Cited by 76
Venkatesan, A. M., Chen, Z., dos Santos, O., Dehnhardt, C. M., Santos, E. D., Ayral‐Kaloustian, S., Mallon, R. G., Hollander, I. J., Feldberg, L. R., Lucas, J., et al. (2010) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2010.07.104 · Cited by 74
Patnaik, A., Ricart, A. D., Cooper, J., et al. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2007.25.18_suppl.3512 · Cited by 72
Immunohistochemical expression of phospho-Akt in uveal melanoma
Saraiva, V. S., Caissie, A. L., Segal, L. M., et al. (2005) · Melanoma Research · doi:10.1097/00008390-200508000-00003 · Cited by 71
Rapamycin induces Smad activity in prostate cancer cell lines
van der Poel, H. G., Hanrahan, C. F., Zhong, H., & Simons, J. W. (2003) · Urological Research · doi:10.1007/s00240-002-0282-1 · Cited by 70
Antibody-Based Profiling of the Phosphoinositide 3-Kinase Pathway in Clinical Prostate Cancer
THOMAS, G. V., Horvath, S., Smith, B. L., et al. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-0130 · Cited by 68
S6K1 Plays a Key Role in Glial Transformation
Nakamura, J. L., Garcia, E., & Pieper, R. O. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-6188 · Cited by 61
Hiramatsu, M., Ninomiya, H., Inamura, K., Nomura, K., Takeuchi, K., Satoh, Y., Okumura, S., Nakagawa, K., Yamori, T., Matsuura, M., et al. (2010) · Lung Cancer · doi:10.1016/j.lungcan.2010.01.001 · Cited by 51
The IκB kinase- a bridge between inflammation and cancer
Michael, M., & Karin (2008) · Acta Scientiarum Naturalium Universitatis Sunyatseni · Cited by 49
mTOR pathway activation in cutaneous melanoma is associated with poorer prognosis characteristics
Pópulo, H., Soares, P., Faustino, A., Rocha, A. S., Silva, P., Azevedo, F., & Lopes, J. M. (2010) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2010.00796.x · Cited by 47
Self-citationNo, J. H., Jeon, Y. T., Park, I.-A., Kim, Y.-B., Kim, J., Park, N.-H., Kang, S., Han, H. J., Lim, J. M., & Song, Y. S. (2011) · Gynecologic Oncology · doi:10.1016/j.ygyno.2010.12.364 · Cited by 46
Resistance to Rapamycin: A Novel Anticancer Drug
Huang, S., & Houghton, P. J. (2001) · Cancer and Metastasis Reviews · doi:10.1023/a:1013167315885 · Cited by 44
Thallinger, C., Poeppl, W., Pratscher, B., Mayerhöfer, M., Valent, P., Tappeiner, G., & Joukhadar, C. (2007) · Pharmacology · doi:10.1159/000101008 · Cited by 42
Merchan, J. R., Pitot, H. C., Qin, R., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.15_suppl.5039 · Cited by 39
Johnson, S. R., & Tattersfield, A. E. (2002) · Seminars in Respiratory and Critical Care Medicine · doi:10.1055/s-2002-25298 · Cited by 38
Werzowa, J. M., Cejka, D., Fuereder, T., Dekrout, B., Thallinger, C., Pehamberger, H., Wacheck, V., & Pratscher, B. (2008) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2008.08991.x · Cited by 36
PTEN expression in renal cell carcinoma and oncocytoma and prognosis
Hager, M., Haufe, H., Kemmerling, R., et al. (2007) · Pathology · doi:10.1080/00313020701570012 · Cited by 32
Usui, I., Haruta, T., Iwata, M., Takano, A., Uno, T., Kawahara, J., Ueno, E., Sasaoka, T., & Kobayashi, M. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.3201 · Cited by 28
Seidel, E. R., & Ragan, V. (1997) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0700936 · Cited by 26
Estrogen and rapamycin effects on cell cycle progression in T47D breast cancer cells
Pang, H., & Faber, L. E. (2001) · Breast Cancer Research and Treatment · doi:10.1023/a:1012570204923 · Cited by 26
McDaid, H. M., Legrier, M., Yang, C. H., et al. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2007.25.18_suppl.10615 · Cited by 6
Simultaneous pancreas-kidney transplantation initial experience
Linhares, M. M., Gonzalez, A. M., Triviño, T., et al. (2003) · Transplantation Proceedings · doi:10.1016/s0041-1345(03)00328-2 · Cited by 5
Targeting the IGF-1/mTOR pathway
Houghton, P. J. (2008) · Clinical Cancer Research · Cited by 3
Abstract PL05-03: Influence of Mother Nature’s pharmacopeia on everyday health and wellbeing
Pezzuto, J. M., & Morris, K. R. (2008) · Cancer Prevention Research · doi:10.1158/1940-6207.prev-08-pl05-03 · Cited by 1
Flagged first, then by citations
Cited by
Sorted by citations
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
