| Title | BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal Cancers |
| Authors | Tang, Zhiyu Yuan, Xi Du, Rong Cheung, Shing-Hu Zhang, Guoliang Wei, Jing Zhao, Yuan Feng, Yingcai Peng, Hao Zhang, Yi Du, Yunguang Hu, Xiaoxia Gong, Wenfeng Liu, Yong Gao, Yajuan Liu, Ye Hao, Rui Li, Shengjian Wang, Shaohui Ji, Jiafu Zhang, Lianhai Li, Shuangxi Sutton, David Wei, Min Zhou, Changyou Wang, Lai Luo, Lusong |
| Affiliation | BeiGene Beijing Co Ltd, Dept In Vivo Pharmacol, Beijing 102206, Peoples R China. BeiGene Beijing Co Ltd, Dept Discovery Biol, Beijing 102206, Peoples R China. BeiGene Beijing Co Ltd, Dept Chem, Beijing 102206, Peoples R China. BeiGene Beijing Co Ltd, Dept Mol Sci, Beijing 102206, Peoples R China. Peking Univ, Canc Hosp & Inst, Dept Surg, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing 100871, Peoples R China. BeiGene Beijing Co Ltd, 30 Sci Pk Rd,Zhong Guan Cun Life Sci Pk, Beijing 102206, Peoples R China. |
| Keywords | ISLAND METHYLATOR PHENOTYPE METASTATIC MELANOMA V600E MUTATION COLON-CANCER VEMURAFENIB ACTIVATION GROWTH CELLS DABRAFENIB CASCADE |
| Issue Date | 2015 |
| Publisher | MOLECULAR CANCER THERAPEUTICS |
| Citation | MOLECULAR CANCER THERAPEUTICS.2015,14,(10),2187-2197. |
| Abstract | Oncogenic BRAF, which drives cell transformation and proliferation, has been detected in approximately 50% of human malignant melanomas and 5% to 15% of colorectal cancers. Despite the remarkable clinical activities achieved by vemurafenib and dabrafenib in treating BRAF(V600E) metastatic melanoma, their clinical efficacy in BRAF(V600E) colorectal cancer is far less impressive. Prior studies suggested that feedback activation of EGFR and MAPK signaling upon BRAF inhibition might contribute to the relative unresponsiveness of colorectal cancer to the first-generation BRAF inhibitors. Here, we report characterization of a dual RAF kinase/EGFR inhibitor, BGB-283, which is currently under clinical investigation. In vitro, BGB-283 potently inhibits BRAF(V600E)-activated ERK phosphorylation and cell proliferation. It demonstrates selective cytotoxicity and preferentially inhibits proliferation of cancer cells harboring BRAF(V600E) and EGFR mutation/amplification. In BRAF(V600E) colorectal cancer cell lines, BGB-283 effectively inhibits the reactivation of EGFR and EGFR-mediated cell proliferation. In vivo, BGB-283 treatment leads to dose-dependent tumor growth inhibition accompanied by partial and complete tumor regressions in both cell line-derived and primary human colorectal tumor xenografts bearing BRAF(V600E) mutation. These findings support BGB-283 as a potent antitumor drug candidate with clinical potential for treating colorectal cancer harboring BRAF(V600E) mutation. (C) 2015 AACR. |
| URI | http://hdl.handle.net/20.500.11897/415886 |
| ISSN | 1535-7163 |
| DOI | 10.1158/1535-7163.MCT-15-0262 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 北京肿瘤医院 |
