Mirone Giovanna, Perna Stefania, Shukla Arvind, Marfe Gabriella
Department of Medical Oncology B, Regina Elena National Cancer Institute, via Elio Chianesi 53, Rome, Italy.
Department of Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Second University of Naples, via Vivaldi 43, Caserta, Italy.
J Cell Physiol. 2016 May;231(5):1097-105. doi: 10.1002/jcp.25206. Epub 2015 Oct 8.
Regorafenib, an oral small-molecule multi kinase inhibitor, is able to block Vascular Endothelial Growth Factor Receptors (VEGFR-1, 2, and 3), Platelet-Derived Growth Factor Receptors (PDGF), Fibroblast Growth Factor (FGF) receptor 1, Raf, TIE-2, and the kinases KIT, RET, and BRAF. Different studies have displayed its antitumor activity in several cancer models (both in vitro and in vivo), particularly in colorectal and gastrointestinal stromal cancers. The mechanism of resistance to regorafenib is largely unknown. In our investigation, we have generated regorafenib-resistant SW480 cells (Reg-R-SW480 cells) by culturing such cells with increasing concentration of regorafenib. Examination of intracellular signaling found that Akt signaling was activated in Reg-R-SW480 cells but not in wild-type SW480 cells, after regorafenib treatment as measured by Western Blot. The Notch pathway is a fundamental signaling system in the development and homeostasis of tissues since it regulates different cellular process such as proliferation, differentiation, and apoptosis and it can be a potential driver of resistance to a wide array of targeted therapies. In this study, we found that Notch-1 was significantly up-regulated in resistant tumor cells as well as HES1 and HEY. Additionally, inhibition of Notch-1 in resistant cells partially restored sensitivity to regorafenib treatment in vitro. Collectively, these data suggest a key role of Notch-1 in mediating the resistant effects of regorafenib in colorectal cancer cells, and also provide a rationale to improve the therapeutic efficacy of regorafenib.
瑞戈非尼是一种口服小分子多激酶抑制剂，能够阻断血管内皮生长因子受体（VEGFR-1、2和3）、血小板衍生生长因子受体（PDGF）、成纤维细胞生长因子（FGF）受体1、Raf、TIE-2以及激酶KIT、RET和BRAF。不同研究已在多种癌症模型（包括体外和体内模型）中显示出其抗肿瘤活性，尤其是在结直肠癌和胃肠道间质瘤中。对瑞戈非尼耐药的机制在很大程度上尚不清楚。在我们的研究中，通过用浓度递增的瑞戈非尼培养SW480细胞，我们获得了对瑞戈非尼耐药的SW480细胞（Reg-R-SW480细胞）。细胞内信号检测发现，经瑞戈非尼处理后，通过蛋白质免疫印迹法检测发现Reg-R-SW480细胞中的Akt信号被激活，而野生型SW480细胞中未被激活。Notch信号通路是组织发育和内环境稳定中的一个基本信号系统，因为它调节不同的细胞过程，如增殖、分化和凋亡，并且它可能是对多种靶向治疗产生耐药性的潜在驱动因素。在本研究中，我们发现Notch-1在耐药肿瘤细胞以及HES1和HEY中显著上调。此外，在耐药细胞中抑制Notch-1可部分恢复体外对瑞戈非尼治疗的敏感性。总体而言，这些数据表明Notch-1在介导瑞戈非尼对结直肠癌细胞的耐药作用中起关键作用，也为提高瑞戈非尼的治疗效果提供了理论依据。
