Inhibition of Mammalian target of rapamycin by rapamycin causes the regression of carcinogen-induced skin tumor lesions
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Abstract
PURPOSE: The activation of Akt/mammalian target of rapamycin (mTOR) pathway represents a frequent event in squamous cell carcinoma (SCC) progression, thus raising the possibility of using specific mTOR inhibitors for the treatment of SCC patients. In this regard, blockade of mTOR with rapamycin prevents the growth of human head and neck SCC cells when xenotransplanted into immunodeficient mice. However, therapeutic responses in xenograft tumors are not always predictive of clinical anticancer activity. EXPERIMENTAL DESIGN: As genetically defined and chemically induced animal cancer models often reflect better the complexity of the clinical setting, we used here a two-step chemical carcinogenesis model to explore the effectiveness of rapamycin for the treatment of skin SCC. RESULTS: Rapamycin exerted a remarkable anticancer activity in this chemically induced cancer model, decreasing the tumor burden of mice harboring early and advanced tumor lesions, and even recurrent skin SCCs. Immunohistochemical studies on tumor biopsies and clustering analysis revealed that rapamycin causes the rapid decrease in the phosphorylation status of mTOR targets followed by the apoptotic death of cancer cells and the reduction in the growth and metabolic activity of the surviving ones, concomitant with a decrease in the population of cancer cells expressing mutant p53. This approach enabled investigating the relationship among molecular changes caused by mTOR inhibition, thus helping identify relevant biomarkers for monitoring the effectiveness of mTOR inhibition in the clinical setting. CONCLUSIONS: Together, these findings provide a strong rationale for the early evaluation of mTOR inhibitors as a molecular targeted approach to treat SCC.
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Inhibition of mTOR by rapamycin and its derivatives has shown promising antitumoral activity in a variety of experimental models of HNSCC.
“Inhibition of mTOR by the use of rapamycin and its derivatives has shown promising antitumoral activity in a variety of experimental models of HNSCC (Amornphimoltham et al., 2008; Amornphimoltham et al., 2005; Czerninski et al., 2009; Nathan et al., 2007)”
From mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis (2012) · cites this paper as Amornphimoltham et al., 2008
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- Authors
- Amornphimoltham, P., Leelahavanichkul, K., Molinolo, A., Patel, V., & Gutkind, J. S.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Gutkind, J. Silvio
- Venue
- Clinical Cancer Research
- Published
- 2008-12-15
- Volume
- 14
- Issue
- 24
- Pages
- 8094-8101
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC3407681
- OpenAlex
- W2104065210
- Cited by
- 63
- References
- 29
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 1 · 2021: 3 · 2020: 3 · 2019: 5 · 2017: 4 · 2016: 7 · 2015: 6 · 2014: 4 · 2013: 5 · 2012: 9
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Dental and Craniofacial Research (ZIADE000558)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- rapamycin, mTOR inhibition, squamous cell carcinoma, skin cancer, chemical carcinogenesis, tumor regression, Akt/mTOR signaling, mutant p53, apoptosis, tumor markers, targeted cancer therapy
- MeSH terms
- Animals, Antineoplastic Agents, Carrier Proteins, Female, Skin Neoplasms, 9,10-Dimethyl-1,2-benzanthracene, Phosphotransferases (Alcohol Group Acceptor), Sirolimus, Mice, TOR Serine-Threonine Kinases
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