The mammalian target of rapamycin pathway is widely activated without PTEN deletion in renal cell carcinoma metastases
TA Youssif, MA Fahmy, IH Koumakpayi, F Ayala… - Cancer, 2011 - Wiley Online Library
TA Youssif, MA Fahmy, IH Koumakpayi, F Ayala, S Al Marzooqi, G Chen, P Tamboli, J Squire…
Cancer, 2011•Wiley Online LibraryBACKGROUND: 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. METHODS: The authors immunostained metastatic RCC samples from 132 patients …
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. METHODS: The authors immunostained metastatic RCC samples from 132 patients …
BACKGROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
Wiley Online Library