Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation.
BACKGROUND
Because mammalian target of rapamycin (mTOR) inhibitors combine anticancer and immunosuppressive properties we investigated: 1) the activation status and prognostic significance of the mTOR pathway in hepatocellular carcinoma (HCC) tissues of patients undergoing orthotopic liver transplantation (OLT) for HCC, and 2) the single and combinatorial efficacy of RAD001 in HCC cells.


METHODS
PTEN, p-AKT, p-mTOR, p-p70S6K, and p-4EBP-1 were analyzed by immunohistochemistry in explanted HCCs of 166 patients undergoing OLT. Efficacy of RAD001 as mono- and combination therapy with doxorubicin was tested in Hep3B and SNU398 cells.


RESULTS
The mTOR pathway is activated in about 40% of patients undergoing OLT for HCC but no direct correlation between up- and downstream proteins was observed. We found no influence of mTOR pathway protein expression on disease free survival (DFS) or overall survival (OS). There was a marked single agent and chemo-sensitizing effect of RAD001 against HCC cells in vitro.


CONCLUSIONS
The mTOR pathway is active in 40% of patients with HCC undergoing OLT, but has no influence of DFS or OS. No direct correlation was observed between up- and downstream proteins limiting the use of upstream proteins to predict mTOR activity. Prospective clinical trials are needed to test whether the activation status of the mTOR pathway in HCCs predicts the antitumor effect of rapamycin derivative in the posttransplantation course.
Sieghart
Wolfgang
W
Department of Clinical Pharmacology, Section of Experimental Oncology/Molecular Pharmacology, Medical University Vienna, Vienna, Austria.
Fuereder
Thorsten
T
Schmid
Katharina
K
Cejka
Daniel
D
Werzowa
Johannes
J
Wrba
Fritz
F
Wang
Xiaowei
X
Gruber
Diego
D
Rasoul-Rockenschaub
Susanne
S
Peck-Radosavljevic
Markus
M
Wacheck
Volker
V
D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000494:pharmacology; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases
D004317:Doxorubicin; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases