Zhong Lei, Yang Jiao, Cao Zhixing, Chen Xin, Hu Yiguo, Li Linli, Yang Shengyong
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University/Collaborative Innovation Center of Biotherapy, Sichuan 610041, China.
Personalized Drug Therapy Key Laboratory of Sichuan Province, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Sichuan 610072, China.
Oncotarget. 2017 Feb 21;8(8):12843-12854. doi: 10.18632/oncotarget.14597.
Non-small cell lung cancer (NSCLC) is a serious life-threatening malignancy. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as Gefitinib and Erlotinib, are effective clinical medicines for advanced NSCLC patients harboring EGFR-activating mutations. However, this therapy just benefits a small percentage of sufferers. Worse still, all patients treated with drugs ultimately develop resistance. Hence, there is still an unmet medical need among patients with NSCLC. In this account, we report a novel multikinase inhibitor SKLB-178, which potently inhibits both EGFR-activating and resistant mutations, as well as the activities of Src and VEGFR2 kinases. SKLB-178 potently inhibited cancer cell growth in both Gefitinib-sensitive and resistant NSCLC cells. Meanwhile, SKLB-178 significantly suppressed the migration, invasion and tube formation of endothelial cells, and the growth of intersegmental vessel in zebrafish. The in vivo pharmacodynamic studies further demonstrated that SKLB-178 had wider potency than Gefitinib, and could significantly prolong survival of animals in A549 experimental metastasis model. These advantages together with the low toxicity of SKLB-178 indicate that SKLB-178 deserves to be further developed as a potential drug candidate for NSCLC therapy.
非小细胞肺癌（NSCLC）是一种严重威胁生命的恶性肿瘤。表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，如吉非替尼和厄洛替尼，是治疗携带EGFR激活突变的晚期NSCLC患者的有效临床药物。然而，这种疗法仅使一小部分患者受益。更糟糕的是，所有接受药物治疗的患者最终都会产生耐药性。因此，NSCLC患者仍存在未满足的医疗需求。在本报告中，我们报道了一种新型多激酶抑制剂SKLB-178，它能有效抑制EGFR激活突变和耐药突变，以及Src和VEGFR2激酶的活性。SKLB-178能有效抑制吉非替尼敏感和耐药NSCLC细胞中的癌细胞生长。同时，SKLB-178显著抑制内皮细胞的迁移、侵袭和管腔形成，以及斑马鱼节间血管的生长。体内药效学研究进一步表明，SKLB-178的效力比吉非替尼更广，并且在A549实验性转移模型中能显著延长动物的生存期。SKLB-178的这些优势以及低毒性表明，SKLB-178值得作为NSCLC治疗的潜在候选药物进一步开发。
