Journal
ONCOTARGET
Volume 6, Issue 18, Pages 16611-16622Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3425
Keywords
insulin-like growth factor receptor 1; prostate cancer; ETS fusion genes; anti-IGF-1R agents
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Funding
- Italian Ministry of Research and Instruction [RBAP11884 M_005]
- Italian Association for Cancer Research [14049]
- Instituto de Salud Carlos III Madrid, Spain [PI10/01206, FPI11/00505]
- Fondazione Italiana per la Ricerca sul Cancro - FIRC
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Identifying patients who may benefit from targeted therapy is an urgent clinical issue in prostate cancer (PCa). We investigated the molecular relationship between TMPRSS2-ERG (T2E) fusion gene and insulin-like growth factor receptor (IGF-1R) to optimize the use of IGF-1R inhibitors. IGF-1R was analyzed in cell lines and in radical prostatectomy specimens in relation to T2E status. ERG binding to IGF-1R promoter was evaluated by chromatin immunoprecipitation (ChIP). Sensitivity to anti-IGF-1R agents was evaluated alone or in combination with anti-androgen abiraterone acetate in vitro at basal levels or upon ERG modulation. IGF-1R analysis performed in PCa cells or clinical samples showed that T2E expression correlated with higher IGF-1R expression at mRNA and protein levels. Genetic modulation of ERG directly affected IGF-1R protein levels in vitro. ChIP analysis showed that ERG binds IGF-1R promoter and that promoter occupancy is higher in T2E-positive cells. IGF-1R inhibition was more effective in cell lines expressing the fusion gene and combination of IGF-1R inhibitors with abiraterone acetate produced synergistic effects in T2E-expressing cells. Here, we provide the rationale for use of T2E fusion gene to select PCa patients for anti-IGF-1R treatments. The combination of anti-IGF-1R-HAbs with an anti-androgen therapy is strongly advocated for patients expressing T2E.
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