title: ERG deregulation induces IGF-1R expression in prostate cancer cells and affects sensitivity to anti-IGF-1R agents.
abstract: 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.
authors.affiliation: CRS Development of Biomolecular Therapies, Experimental Oncology Lab, Rizzoli Orthopaedic Institute, Bologna, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Mancarella
authors.affiliation: Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Casanova-Salas
authors.affiliation: Department of Pathology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Calatrava
authors.affiliation: CRS Development of Biomolecular Therapies, Experimental Oncology Lab, Rizzoli Orthopaedic Institute, Bologna, Italy.
authors.forename: Selena
authors.initials: S
authors.lastname: Ventura
authors.affiliation: CRS Development of Biomolecular Therapies, Experimental Oncology Lab, Rizzoli Orthopaedic Institute, Bologna, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garofalo
authors.affiliation: Department of Urology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Rubio-Briones
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.
authors.forename: Vera
authors.initials: V
authors.lastname: Magistroni
authors.affiliation: CRS Development of Biomolecular Therapies, Experimental Oncology Lab, Rizzoli Orthopaedic Institute, Bologna, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Manara
authors.affiliation: Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: López-Guerrero
authors.affiliation: CRS Development of Biomolecular Therapies, Experimental Oncology Lab, Rizzoli Orthopaedic Institute, Bologna, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Scotlandi
mesh_terms: D000069501:Abiraterone Acetate / Q000494:pharmacology; D000726:Androgen Antagonists / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D011467:Prostate / Q000473:pathology / Q000601:surgery; D011471:Prostatic Neoplasms / Q000473:pathology*; D011485:Protein Binding; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D000071230:Transcriptional Regulator ERG
chemical_list: D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D017526:Receptor, IGF Type 1; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; D000069501:Abiraterone Acetate
keywords: ETS fusion genes; anti-IGF-1R agents; insulin-like growth factor receptor 1; prostate cancer