Yang Xuran, Xia Wei, Chen Lin, Wu Chuan Xing, Zhang Cathy C, Olson Peter, Wang Xiao Qi
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Oncology Research Unit, Pfizer Global Research and Development, La Jolla, California, USA.
Oncotarget. 2018 Oct 9;9(79):34996-35007. doi: 10.18632/oncotarget.26209.
As a multi-kinase inhibitor, sorafenib is beneficial in around 30% of hepatocellular carcinoma (HCC) patients; however, HCC patients develop acquired drug resistance quickly. Clinical benefits of sorafenib, in combination with transarterial chemoembolization (TACE), radiotherapy, and other chemodrugs are limited. We investigated the efficacy and mechanisms of Notch signaling inhibition as adjuvant to sorafenib in HCC spheroid-derived and tumor models, using the γ-secretase inhibitor (GSI), PF-03084014. The combination of PF-03084014 plus sorafenib inhibited proliferation and self-renewal of HCC spheroids (stem-like cancer cells). PF-03084014 significantly enhanced antitumor activity of sorafenib; both agents at low dose reached synergistic tumor growth suppression of HCC spheroid-derived orthotopic tumors. The Notch1-Snail1 signaling pathway contributed to sorafenib resistance via increasing epithelial-mesenchymal transition (EMT) and EMT-mediated cancer stem cell (CSC) features, such as increased expression of Snail1, N-cadherin, ABCG2, and the stem cell related genes Nanog and Oct4, and decreased expression of E-cadherin. Anti-tumor activity of the combination therapy was associated with decreased expression of survival signals (Mek/Erk, PI3K/Akt) and reduced microvessel density. PF-03084014 plus sorafenib targets Notch1-Snail1 signaling to reverse EMT and EMT-mediated CSC stemness in the tumors. These synergistic effects provide a rationale to utilize GSIs, in combination with sorafenib, as a new therapeutic strategy for the treatment of HCC.
作为一种多激酶抑制剂，索拉非尼对约30%的肝细胞癌（HCC）患者有益；然而，HCC患者会迅速产生获得性耐药。索拉非尼与经动脉化疗栓塞（TACE）、放疗及其他化疗药物联合使用的临床益处有限。我们使用γ-分泌酶抑制剂（GSI）PF-03084014，研究了Notch信号通路抑制作为索拉非尼辅助治疗在HCC球体衍生模型和肿瘤模型中的疗效及机制。PF-03084014与索拉非尼联合使用可抑制HCC球体（干细胞样癌细胞）的增殖和自我更新。PF-03084014显著增强了索拉非尼的抗肿瘤活性；两种药物低剂量联合使用对HCC球体衍生的原位肿瘤具有协同的肿瘤生长抑制作用。Notch1-Snail1信号通路通过增加上皮-间质转化（EMT）以及EMT介导的癌症干细胞（CSC）特征，如Snail1、N-钙黏蛋白、ABCG2以及干细胞相关基因Nanog和Oct4的表达增加，E-钙黏蛋白表达降低，从而导致索拉非尼耐药。联合治疗的抗肿瘤活性与生存信号（Mek/Erk、PI3K/Akt）表达降低及微血管密度降低有关。PF-03084014与索拉非尼联合靶向Notch1-Snail1信号通路，以逆转肿瘤中的EMT及EMT介导的CSC干性。这些协同效应为将GSIs与索拉非尼联合作为治疗HCC的新治疗策略提供了理论依据。
