Liu Rujiao, Tang Wenbo, Han Xiaotian, Geng Ruixuan, Wang Chenchen, Zhang Zhe
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China.
Oncol Lett. 2018 Nov;16(5):5983-5991. doi: 10.3892/ol.2018.9414. Epub 2018 Sep 6.
Insulin-like growth factor 1 receptor (IGF-1R) inhibitors have been developed as potential therapeutics for cancer treatment; however, the phase III trials have not produced promising overall survival rates. Therefore, understanding the mechanism underlying intrinsic resistance to IGF-1R-targeted agents is urgently required. A number of studies have revealed that activation of alternative receptor tyrosine kinases can mediate resistance to IGF-1R-targeted therapy. The present study investigated whether activated mesenchymal-epithelial transition factor (MET; also known as c-Met and hepatocyte growth factor receptor) confers resistance to an IGF-1R inhibitor (NVP-AEW541) of gastric cancer (GC) cells. NCI-N87 and MGC-803 cells were treated with varying concentrations and combinations of NVP-AEW541, hepatocyte growth factor (HGF) and MET small interfering (si)-RNA or crizotinib (a MET inhibitor). The effects of these agents on cell proliferation and pro-apoptotic events were assessed by Cell Counting Kit-8 assays and flow cytometry. Receptor activation and the downstream signaling pathway were examined using western blot analysis. Expression and/or activation of MET and IGF-1R in 156 GC specimens were evaluated by immunohistochemistry. The results demonstrated that NVP-AEW541 inhibited cell growth, with dephosphorylation of IGF-1R and protein kinase B (AKT), in NCI-N87 and MGC-803 cells. Application of HGF activated MET and the downstream AKT signaling pathways, decreased apoptotic events and restored cell proliferation, which were reversed by MET inhibition via crizotinib or siRNA knockdown. Furthermore, combination therapy of NVP-AEW541 and crizotinib exhibited an enhanced effectiveness . In addition, >40% of IGF-1R overexpressed GC specimens showed MET expression and activation. In conclusion, HGF-induced MET activation may represent a novel mechanism conferring unresponsiveness to IGF-1R-targeted agents in GC, and inhibition of MET may improve the efficacy of IGF-1R inhibitors.
胰岛素样生长因子1受体（IGF-1R）抑制剂已被开发作为癌症治疗的潜在疗法；然而，III期试验并未产生令人满意的总生存率。因此，迫切需要了解对IGF-1R靶向药物内在抗性的潜在机制。许多研究表明，替代受体酪氨酸激酶的激活可介导对IGF-1R靶向治疗的抗性。本研究调查了激活的间充质-上皮转化因子（MET；也称为c-Met和肝细胞生长因子受体）是否赋予胃癌（GC）细胞对IGF-1R抑制剂（NVP-AEW541）的抗性。用不同浓度和组合的NVP-AEW541、肝细胞生长因子（HGF）和MET小干扰（si）RNA或克唑替尼（一种MET抑制剂）处理NCI-N87和MGC-803细胞。通过细胞计数试剂盒-8测定法和流式细胞术评估这些药物对细胞增殖和促凋亡事件的影响。使用蛋白质印迹分析检查受体激活和下游信号通路。通过免疫组织化学评估156例GC标本中MET和IGF-1R的表达和/或激活。结果表明，NVP-AEW541抑制NCI-N87和MGC-803细胞的生长，同时使IGF-1R和蛋白激酶B（AKT）去磷酸化。HGF的应用激活了MET和下游AKT信号通路，减少了凋亡事件并恢复了细胞增殖，而通过克唑替尼或siRNA敲低抑制MET可逆转这些变化。此外，NVP-AEW541和克唑替尼的联合治疗显示出增强的效果。此外，超过40%的IGF-1R过表达GC标本显示MET表达和激活。总之，HGF诱导的MET激活可能是GC中对IGF-1R靶向药物无反应的一种新机制，抑制MET可能提高IGF-1R抑制剂的疗效。
