Zhang Ruo-Yu, Yu Zhi-Hong, Zeng Lifan, Zhang Sheng, Bai Yunpeng, Miao Jinmin, Chen Lan, Xie Jingwu, Zhang Zhong-Yin
Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Oncotarget. 2016 Nov 8;7(45):73817-73829. doi: 10.18632/oncotarget.12074.
Melanoma ranks among the most aggressive and deadly human cancers. Although a number of targeted therapies are available, they are effective only in a subset of patients and the emergence of drug resistance often reduces durable responses. Thus there is an urgent need to identify new therapeutic targets and develop more potent pharmacological agents for melanoma treatment. Herein we report that SHP2 levels are frequently elevated in melanoma, and high SHP2 expression is significantly associated with more metastatic phenotype and poorer prognosis. We show that SHP2 promotes melanoma cell viability, motility, and anchorage-independent growth, through activation of both ERK1/2 and AKT signaling pathways. We demonstrate that SHP2 inhibitor 11a-1 effectively blocks SHP2-mediated ERK1/2 and AKT activation and attenuates melanoma cell viability, migration and colony formation. Most importantly, SHP2 inhibitor 11a-1 suppresses xenografted melanoma tumor growth, as a result of reduced tumor cell proliferation and enhanced tumor cell apoptosis. Taken together, our data reveal SHP2 as a novel target for melanoma and suggest SHP2 inhibitors as potential novel therapeutic agents for melanoma treatment.
黑色素瘤是最具侵袭性和致命性的人类癌症之一。尽管有多种靶向疗法可供使用，但它们仅对一部分患者有效，而且耐药性的出现常常会降低持久疗效。因此，迫切需要确定新的治疗靶点，并开发更有效的药物用于黑色素瘤治疗。在此我们报告，SHP2水平在黑色素瘤中经常升高，高SHP2表达与更具转移的表型和更差的预后显著相关。我们表明，SHP2通过激活ERK1/2和AKT信号通路促进黑色素瘤细胞的活力、运动能力和非锚定依赖性生长。我们证明，SHP2抑制剂11a-1有效阻断SHP2介导的ERK1/2和AKT激活，并减弱黑色素瘤细胞的活力、迁移和集落形成。最重要的是，SHP2抑制剂11a-1抑制异种移植黑色素瘤肿瘤的生长，这是由于肿瘤细胞增殖减少和肿瘤细胞凋亡增强所致。综上所述，我们的数据揭示SHP2是黑色素瘤的一个新靶点，并表明SHP2抑制剂是黑色素瘤治疗的潜在新型治疗药物。
