Mancarella Caterina, Casanova-Salas Irene, Calatrava Ana, Ventura Selena, Garofalo Cecilia, Rubio-Briones José, Magistroni Vera, Manara Maria Cristina, López-Guerrero José Antonio, Scotlandi Katia
CRS Development of Biomolecular Therapies, Experimental Oncology Lab, Rizzoli Orthopaedic Institute, Bologna, Italy.
Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
Oncotarget. 2015 Jun 30;6(18):16611-22. doi: 10.18632/oncotarget.3425.
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.
识别可能从靶向治疗中获益的前列腺癌（PCa）患者是一个紧迫的临床问题。我们研究了跨膜丝氨酸蛋白酶2-ETS相关基因（TMPRSS2-ERG，T2E）融合基因与胰岛素样生长因子受体（IGF-1R）之间的分子关系，以优化IGF-1R抑制剂的使用。在细胞系和前列腺癌根治术标本中分析IGF-1R与T2E状态的关系。通过染色质免疫沉淀（ChIP）评估ERG与IGF-1R启动子的结合。在基础水平或ERG调节后，在体外单独或与抗雄激素醋酸阿比特龙联合评估对抗IGF-1R药物的敏感性。在PCa细胞或临床样本中进行的IGF-1R分析表明，T2E表达在mRNA和蛋白质水平上与较高的IGF-1R表达相关。ERG的基因调节在体外直接影响IGF-1R蛋白水平。ChIP分析表明，ERG结合IGF-1R启动子，且在T2E阳性细胞中启动子占有率更高。IGF-1R抑制在表达融合基因的细胞系中更有效，并且IGF-1R抑制剂与醋酸阿比特龙联合在表达T2E的细胞中产生协同效应。在此，我们提供了使用T2E融合基因来选择PCa患者进行抗IGF-1R治疗的理论依据。对于表达T2E的患者，强烈主张将抗IGF-1R单克隆抗体与抗雄激素治疗联合使用。
