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Updated: Jul 15, 2026

A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for
Allan J Pantuck1, David B Seligson, Tobias Klatte
1Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
Background:
The mammalian target of rapamycin (mTOR) pathway is up-regulated in many human cancers, and agents targeting the mTOR pathway are in various stages of clinical development. The goal of the study was to evaluate the potential and limitations of targeting the mTOR pathway in renal cell carcinoma (RCC).
Methods:
Immunohistochemical analysis using antibodies against pAkt, PTEN, p27, and pS6 was performed on a tissue microarray constructed from paraffin-embedded specimens from 375 patients treated by nephrectomy for RCC. The expression was associated with pathological parameters and survival.
Results:
The mTOR pathway was more significantly altered in clear-cell RCC, high-grade tumors, and tumors with poor prognostic features. PS6 and PTEN showed the strongest associations with pathological parameters. Survival tree analysis regarding expression of cytoplasmic pAkt, nuclear pAkt, PTEN, cytoplasmic p27, and pS6 identified staining percentages of 40%, 10%, 75%, 7%, and 70%, respectively, as ideal cutoff values for stratification, with corresponding P-values of .03, .001, .02, .005, and <.0001, respectively. Interestingly, high nuclear pAkt expression was associated with a favorable prognosis, whereas high cytoplasmic pAkt expression was associated with a poor prognosis. In multivariate Cox regression analysis, ECOG PS, T classification, N classification, M classification, cytoplasmic Akt, nuclear pAkt, PTEN, and pS6 were independent prognostic factors of DSS.
Conclusions:
Components of the mTOR pathway are significantly associated with pathological features and survival. Not all RCC tumor types seem to be equally amenable to mTOR targeted therapy. PTEN, pAkt, p27, and pS6 may serve as surrogate parameters for patient selection and predicting prognosis. Patients with a highly activated mTOR pathway should benefit most from this therapy. External validation of our results is recommended.
Insights
Targeting the mammalian target of rapamycin (mTOR) pathway in renal cell carcinoma (RCC) shows promise. Biomarkers like PTEN and pAkt can predict prognosis and patient selection for mTOR-targeted therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The mammalian target of rapamycin (mTOR) pathway is frequently dysregulated in human cancers.
- Targeting the mTOR pathway is a promising therapeutic strategy currently under clinical investigation.
- Renal cell carcinoma (RCC) represents a significant area for evaluating mTOR pathway inhibitors.
Purpose of the Study:
- To investigate the role and potential of targeting the mTOR pathway in renal cell carcinoma (RCC).
- To identify biomarkers within the mTOR pathway associated with RCC pathology and patient survival.
- To assess the limitations and potential of mTOR-targeted therapies in RCC.
Main Methods:
- Immunohistochemical analysis of pAkt, PTEN, p27, and pS6 expression in 375 RCC patient specimens.
- Tissue microarray construction from paraffin-embedded tumor samples.
- Correlation of protein expression with pathological parameters and patient survival data.
Main Results:
- mTOR pathway alterations were more pronounced in clear-cell RCC, high-grade tumors, and those with poor prognostic features.
- PTEN and pS6 expression strongly correlated with pathological parameters.
- Specific expression levels of cytoplasmic pAkt, nuclear pAkt, PTEN, p27, and pS6 served as significant prognostic indicators for patient survival.
- High nuclear pAkt expression indicated a favorable prognosis, while high cytoplasmic pAkt indicated a poor prognosis.
Conclusions:
- mTOR pathway components are significantly linked to RCC pathological characteristics and survival outcomes.
- The efficacy of mTOR-targeted therapy may vary across different RCC subtypes.
- PTEN, pAkt, p27, and pS6 can function as biomarkers for patient selection and prognosis prediction in RCC.
- Patients with highly activated mTOR pathways are likely to benefit most from targeted interventions.
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