State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin, China.
Mol Cancer Ther. 2015 Feb;14(2):407-18. doi: 10.1158/1535-7163.MCT-14-0485. Epub 2014 Dec 17.
The clinical prognosis of pancreatic cancer remains rather disappointing despite tremendous efforts in exploring medical treatments in the past two decades. Development of more effective treatment strategies is still desperately needed to improve outcomes in patients with pancreatic cancer. SKLB261 is a multikinase inhibitor obtained recently through a lead optimization. In this investigation, we shall evaluate its anti-pancreatic cancer effects both in vitro and in vivo. SKLB261 is a multikinase inhibitor potently inhibiting EGFR, Src, and VEGFR2 kinases. It could significantly inhibit cell proliferation, migration, and invasion, and induce apoptosis in cellular assays of human pancreatic cancer cells that are sensitive or resistant to dasatinib and/or gemcitabine. Western blot analysis showed that SKLB261 inhibited the activation of EGFR and Src kinases as well as their downstream signaling proteins, including FAK, ERK, and STAT3. SKLB261 also showed potent antiangiogenic effects in transgenic zebrafish models. In vivo, SKLB261 displayed more potent antitumor activities than dasatinib, gemcitabine, or erlotinib in pancreatic cancer xenografts, including BxPC-3, PANC-1, AsPC-1, and HPAC. Furthermore, mice receiving SKLB261 therapy showed significant survival advantage compared with vehicle-treated and gemcitabine-treated groups in an experimental metastasis model of pancreatic cancer. These data, together with the good pharmacokinetic properties and low toxicity of this compound, provide a rationale for the ongoing clinical evaluation of SKLB261 in the treatment of pancreatic cancer.
尽管在过去的二十年中，人们在探索医学治疗方法方面付出了巨大的努力，但胰腺癌的临床预后仍然相当令人失望。仍然迫切需要开发更有效的治疗策略，以改善胰腺癌患者的预后。SKLB261 是最近通过先导优化获得的多激酶抑制剂。在这项研究中，我们将评估其在体外和体内对胰腺癌的治疗效果。SKLB261 是一种多激酶抑制剂，能够强烈抑制 EGFR、Src 和 VEGFR2 激酶。它可以显著抑制细胞增殖、迁移和侵袭，并诱导对达沙替尼和/或吉西他滨敏感或耐药的人胰腺癌细胞系的细胞凋亡。Western blot 分析表明，SKLB261 抑制了 EGFR 和 Src 激酶及其下游信号蛋白，包括 FAK、ERK 和 STAT3 的激活。SKLB261 还在转基因斑马鱼模型中显示出强大的抗血管生成作用。在体内，SKLB261 在胰腺癌细胞异种移植模型中显示出比达沙替尼、吉西他滨或厄洛替尼更强的抗肿瘤活性，包括 BxPC-3、PANC-1、AsPC-1 和 HPAC。此外，与接受载体治疗和吉西他滨治疗的组相比，接受 SKLB261 治疗的小鼠在胰腺癌实验转移模型中显示出显著的生存优势。这些数据，加上该化合物良好的药代动力学特性和低毒性，为 SKLB261 在胰腺癌治疗中的临床评估提供了依据。
