BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal Cancers
| Autor: | Rui Hao, Rong Du, Hao Peng, Xi Yuan, Wenfeng Gong, Changyou Zhou, Wang Shaohui, Ye Liu, Shuangxi Li, Min Wei, Lai Wang, Yajuan Gao, Zhiyu Tang, Yingcai Feng, Shengjian Li, Guoliang Zhang, David Sutton, Jing Wei, Yong Liu, Yunguang Du, Xiaoxia Hu, Lusong Luo, Yuan Zhao, Jiafu Ji, Shing Hu Cheung, Lianhai Zhang, Yi Zhang |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Proto-Oncogene Proteins B-raf Cancer Research endocrine system diseases MAP Kinase Signaling System Colorectal cancer Cell Mice Nude Antineoplastic Agents Mice SCID Biology Mice Inbred NOD Catalytic Domain Cell Line Tumor medicine Animals Humans Naphthyridines Phosphorylation Extracellular Signal-Regulated MAP Kinases Vemurafenib neoplasms Cell Proliferation EGFR inhibitors Mice Inbred BALB C Cell growth Dabrafenib medicine.disease Xenograft Model Antitumor Assays digestive system diseases Tumor Burden ErbB Receptors medicine.anatomical_structure Oncology Cancer cell Immunology Cancer research Benzimidazoles Female raf Kinases Colorectal Neoplasms Protein Processing Post-Translational V600E Protein Binding medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 14:2187-2197 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-15-0262 |
| Popis: | 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 BRAFV600E metastatic melanoma, their clinical efficacy in BRAFV600E 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 BRAFV600E-activated ERK phosphorylation and cell proliferation. It demonstrates selective cytotoxicity and preferentially inhibits proliferation of cancer cells harboring BRAFV600E and EGFR mutation/amplification. In BRAFV600E 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 BRAFV600E mutation. These findings support BGB-283 as a potent antitumor drug candidate with clinical potential for treating colorectal cancer harboring BRAFV600E mutation. Mol Cancer Ther; 14(10); 2187–97. ©2015 AACR. |
| Databáze: | OpenAIRE |
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