ERG deregulation induces IGF-1R expression in prostate cancer cells and affects sensitivity to anti-IGF-1R agents

Caterina Mancarella, Irene Casanova-Salas, Ana Calatrava, Selena Ventura, Cecilia Garofalo, José Rubio-Briones, Vera Magistroni, Maria Cristina Manara, José Antonio López-Guerrero, Katia Scotlandi

Research output: Contribution to journalArticlepeer-review

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 antiandrogen therapy is strongly advocated for patients expressing T2E.

Original languageEnglish
Pages (from-to)16611-16622
Number of pages12
JournalOncotarget
Volume6
Issue number18
Publication statusPublished - 2015

Keywords

  • Anti-IGF-1R agents
  • ETS fusion genes
  • Insulin-like growth factor receptor 1
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology

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