Fahrenholtz Cale D, Greene Ann M, Beltran Pedro J, Burnstein Kerry L
Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, FL, USA.
Oncology Research, Amgen Inc., Thousand Oaks, CA.
Oncotarget. 2014 Oct 15;5(19):9007-21. doi: 10.18632/oncotarget.2346.
Inhibition of the mitogenic insulin-like growth factor receptor 1 (IGF-1R) signaling axis is a compelling treatment strategy for prostate cancer. Combining the IGF-1R inhibitor ganitumab (formerly AMG 479) with standard of care androgen-deprivation therapy greatly delays prostate cancer recurrence in xenograft models; however, a significant proportion of these tumors ultimately acquire resistance to ganitumab. Here we describe the development of a stable and reproducible ganitumab-resistant VCaP human prostate cancer cell derivative termed VCaP/GanR to investigate the mechanism of acquired resistance to IGF-1R inhibition. Unlike parental VCaP, VCaP/GanR did not undergo apoptosis following ganitumab treatment. VCaP/GanR did not express increased levels of IGF-1R, insulin receptor, or phospho-AKT compared to parental VCaP. VCaP/GanR exhibited increased levels of phospho-S6 indicative of increased mTOR activity. However, acquired resistance to ganitumab was not dependent on increased mTOR activity in VCaP/GanR. Phospho-proteomic arrays revealed alterations in several calcium-regulated signaling components in VCaP/GanR compared to VCaP. Reduction of intracellular calcium using cell-permeable calcium-specific chelators restored ganitumab sensitivity to VCaP/GanR through inhibition of cell-cycle progression. These data suggest a new mechanism of resistance to IGF-1R inhibition involving calcium-mediated proliferation effects. Such pathways should be considered in future clinical studies of IGF-1R inhibitors in prostate cancer.
抑制有丝分裂的胰岛素样生长因子受体1（IGF-1R）信号轴是一种极具吸引力的前列腺癌治疗策略。将IGF-1R抑制剂ganitumab（原名AMG 479）与标准护理雄激素剥夺疗法相结合，可在异种移植模型中大大延迟前列腺癌的复发；然而，这些肿瘤中有很大一部分最终会对ganitumab产生耐药性。在此，我们描述了一种稳定且可重复的对ganitumab耐药的VCaP人前列腺癌细胞衍生物的产生，称为VCaP/GanR，以研究对IGF-1R抑制产生获得性耐药的机制。与亲代VCaP不同，VCaP/GanR在接受ganitumab治疗后未发生凋亡。与亲代VCaP相比，VCaP/GanR的IGF-1R、胰岛素受体或磷酸化AKT水平并未升高。VCaP/GanR的磷酸化S6水平升高，表明mTOR活性增强。然而，对ganitumab的获得性耐药并不依赖于VCaP/GanR中mTOR活性的增加。磷酸化蛋白质组阵列显示，与VCaP相比，VCaP/GanR中几种钙调节信号成分发生了改变。使用细胞可渗透的钙特异性螯合剂降低细胞内钙水平，通过抑制细胞周期进程恢复了VCaP/GanR对ganitumab的敏感性。这些数据提示了一种对IGF-1R抑制产生耐药的新机制，涉及钙介导的增殖效应。在未来前列腺癌IGF-1R抑制剂的临床研究中应考虑此类途径。
