title: BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal Cancers.
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.
authors.affiliation: Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Department of Discovery Biology, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Xi
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Discovery Biology, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Rong
authors.initials: R
authors.lastname: Du
authors.affiliation: Department of Discovery Biology, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Shing-Hu
authors.initials: SH
authors.lastname: Cheung
authors.affiliation: Department of Chemistry, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Discovery Biology, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Discovery Biology, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Molecular Sciences, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Yingcai
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Molecular Sciences, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Peng
authors.affiliation: Department of Molecular Sciences, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Molecular Sciences, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Yunguang
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Molecular Sciences, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Molecular Sciences, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Rui
authors.initials: R
authors.lastname: Hao
authors.affiliation: Department of Molecular Sciences, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Shengjian
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Chemistry, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Shaohui
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery, Peking University Cancer Hospital and Institute, Beijing, P.R. China.
authors.forename: Jiafu
authors.initials: J
authors.lastname: Ji
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery, Peking University Cancer Hospital and Institute, Beijing, P.R. China.
authors.forename: Lianhai
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery, Peking University Cancer Hospital and Institute, Beijing, P.R. China.
authors.forename: Shuangxi
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: David
authors.initials: D
authors.lastname: Sutton
authors.affiliation: Department of Molecular Sciences, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.affiliation: Department of Chemistry, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Changyou
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of In Vivo Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China.
authors.forename: Lai
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Discovery Biology, BeiGene (Beijing) Co., Ltd., Beijing, P.R. China. lusong.luo@beigene.com.
authors.forename: Lusong
authors.initials: L
authors.lastname: Luo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008958:Models, Molecular; D009287:Naphthyridines / Q000494:pharmacology*; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D048490:raf Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C000609386:BGB-283; D001562:Benzimidazoles; D009287:Naphthyridines; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases