The mammalian target of rapamycin pathway is widely activated without PTEN deletion in renal cell carcinoma metastases.
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.
Abou Youssif
Tamer
T
Department of Urology, McGill University Health Center, Montreal, Quebec, Canada.
Fahmy
Mona Alam
MA
Koumakpayi
Ismael Herve
IH
Ayala
Fernanda
F
Al Marzooqi
Saeeda
S
Chen
Guangyong
G
Tamboli
Pheroze
P
Squire
Jeremy
J
Tanguay
Simon
S
Sircar
Kanishka
K
D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011379:Prognosis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D059016:Tumor Microenvironment; D015854:Up-Regulation
C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human