The second and third authors contributed equally to this article.
The mammalian target of rapamycin pathway is widely activated without PTEN deletion in renal cell carcinoma metastases
Version of Record online: 9 SEP 2010
Copyright © 2010 American Cancer Society
Volume 117, Issue 2, pages 290–300, 15 January 2011
How to Cite
Youssif, T. A., Fahmy, M. A., Koumakpayi, I. H., Ayala, F., Al Marzooqi, S., Chen, G., Tamboli, P., Squire, J., Tanguay, S. and Sircar, K. (2011), The mammalian target of rapamycin pathway is widely activated without PTEN deletion in renal cell carcinoma metastases. Cancer, 117: 290–300. doi: 10.1002/cncr.25402
- Issue online: 5 JAN 2011
- Version of Record online: 9 SEP 2010
- Manuscript Accepted: 23 MAR 2010
- Manuscript Revised: 19 FEB 2010
- Manuscript Received: 20 NOV 2009
- renal cell carcinoma;
- mammalian target of rapamycin;
- targeted therapy;
Inhibitors of the mammalian target of rapamycin (mTOR) are emerging as promising therapies for metastatic renal cell carcinoma (RCC). Because rational treatment strategies require understanding the activation status of the underlying signaling pathway being targeted at the desired stage of disease, the authors examined the activation status of different components of the mTOR pathway in RCC metastases and matched primary tumors.
The authors immunostained metastatic RCC samples from 132 patients and a subset of 25 matched primary RCCs with antibodies against phosphatidylinositol 3′-kinase, PTEN, phospho-Akt, phospho-mTOR, and p70S6. PTEN genomic status was assessed by fluorescent in situ hybridization. Marker expression was correlated to clinicopathologic variables and to survival.
The mTOR pathway showed widespread activation in RCC metastases of various sites with strong correlation between different components of this signaling cascade (P<.0001), but without significant PTEN genomic deletion. Only cytoplasmic phospho-mTOR showed independent prognostic significance (P = .029) and fidelity between primary RCCs and their matched metastases (P = .004).
Activation of various components of the mTOR signaling pathway in metastatic RCC lesions across various tumor histologies, nuclear grades, and metastatic sites suggests the potential for vertical blockade of multiple steps of this pathway. Patient selection may be improved by mTOR immunostaining of primary RCC. Cancer 2011. © 2010 American Cancer Society.