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.
Highlights
Chromosomal translocations are genetic lesions that are produced by illegitimate recombination events between two non-homologous chromosomes or within the same chromosome and that result in chimeric genes [1]
The intensity of insulin-like growth factor (IGF)-1R immunostaining has generally been reported to increase from benign prostatic hyperplasia (BPH) to prostatic intraepithelial neoplasia (PIN) to carcinoma [16], several studies have not confirmed this linear relationship and have reported that reduced IGF-1 receptor (IGF-1R) is associated with hyperplasia and proliferation or metastatic lesions [17, 18]
The T2E fusion gene constitutes a critical event in development of prostate cancer (PCa) [2, 28], but other genetic alterations, such as loss of PTEN and PI3K pathway activation, are required to induce malignant transformation [8]
Summary
Chromosomal translocations are genetic lesions that are produced by illegitimate recombination events between two non-homologous chromosomes or within the same chromosome and that result in chimeric genes [1]. The intensity of IGF-1R immunostaining has generally been reported to increase from benign prostatic hyperplasia (BPH) to PIN to carcinoma [16], several studies have not confirmed this linear relationship and have reported that reduced IGF-1R is associated with hyperplasia and proliferation or metastatic lesions [17, 18]. Despite this variation may be due to technical factors, clinical studies evaluating the prognostic role of IGF-1R expression have provided controversial results, reporting either positive or negative associations between receptor expression levels and patient outcome [19, 20]. We demonstrated that T2E directly binds the IGF-1R gene promoter, affecting its expression and treatment sensitivity in PCa
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