ERG deregulation induces IGF-1R expression in prostate cancer cells and affects sensitivity to anti-IGF-1R agents
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Caterina Mancarella1, Irene Casanova-Salas2, Ana Calatrava3, Selena Ventura1, Cecilia Garofalo1, José Rubio-Briones4, Vera Magistroni5, Maria Cristina Manara1, José Antonio López-Guerrero2,*, Katia Scotlandi1,*
1CRS Development of Biomolecular Therapies, Experimental Oncology Lab, Rizzoli Orthopaedic Institute, Bologna, Italy
2Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain
3Department of Pathology, Fundación Instituto Valenciano de Oncología, Valencia, Spain
4Department of Urology, Fundación Instituto Valenciano de Oncología, Valencia, Spain
5Department of Health Sciences, University of Milano-Bicocca, Monza, Italy
*These authors have shared senior authorship
Katia Scotlandi, e-mail: [email protected]
Keywords: insulin-like growth factor receptor 1, prostate cancer, ETS fusion genes, anti-IGF-1R agents
Received: November 04, 2014 Accepted: February 23, 2015 Published: March 27, 2015
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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