mTOR pathway activation is a favorable prognostic factor in human prostate adenocarcinoma.
Prostate cancer patients with localized disease are treated with curative intent. However, the disease will recur in approximately 30% of patients with a high incidence of morbidity and mortality. Prognostic biomarkers are needed to identify patients with high risk of relapse. mTOR pathway activation is reported in prostate cancer, but clinical trials testing efficacy of mTOR inhibitors were unsuccessful. To explain this clinical observation, we studied the expression and prognostic impact of mTOR-S2448 phosphorylation in localized prostate carcinomas. mTOR-S2448 phosphorylation is indicative for an activated mTOR pathway in prostate cancer. Surprisingly, the mTOR signaling pathway is activated specifically in prostate cancer patients with a favorable outcome. Since tumors from poor-outcome patients have low levels of mTOR-S2448 phosphorylation, this may explain why mTOR inhibitors proved unsuccessful in prostate cancer trials.
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Suzan
S
Stelloo
Division of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Joyce
J
Sanders
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Ekaterina
E
Nevedomskaya
Division of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Jeroen
J
de Jong
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Dennis
D
Peters
Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
Geert J L H
GJ
van Leenders
Department of Urology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
Guido
G
Jenster
Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Andries M
AM
Bergman
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Wilbert
W
Zwart
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D004789:Enzyme Activation; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010766:Phosphorylation; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D012307:Risk Factors; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
ERG; PI3K pathway; mTOR; prognosis; prostate cancer