Abstract 4692: BGB-283, a novel RAF kinase and EGFR dual inhibitor, displays potent antitumor activity in B-RAF mutated colorectal cancers

Oncogenic B-RAF, which drives cell transformation and proliferation, has been detected in approximately 70% of human malignant melanomas and 5-15% of colorectal cancers (CRC). B-RAFV600E mutation, which gives rise to constitutive MAPK signaling, accounts for at least 90% of oncogenic B-RAF mutations. Despite the remarkable clinical activities achieved by vemurafenib and dabrafenib in treating B-RAFV600E metastatic melanoma, their clinical efficacy in B-RAFV600E CRC is far less impressive. Prior studies suggested that feedback activation of EGFR and MAPK signaling upon B-RAF inhibition contributed to the intrinsic resistance of CRC to the first generation B-RAF inhibitors. This report represents the first characterization of a dual RAF kinase/EGFR inhibitor, BGB-283, which is currently under clinical investigations. BGB-283 is a potent and selective pan-RAF and EGFR inhibitor with IC50 ranging from 5 to 47 nM on RAF and EGFR kinases. In vitro, BGB-283 potently inhibits B-RAFV600E-activated ERK phosphorylation and cell proliferation. It demonstrates selective cytotoxicity and preferentially inhibits proliferation of cancer cells harbouring B-RAFV600E and EGFR mutation/amplification. In B-RAFV600E CRC cell lines, BGB-283 effectively inhibits the reactivation of EGFR and achieved sustained inhibition of MAPK pathway. In vivo, BGB-283 is highly efficacious in inhibiting tumor growth accompanied by partial and complete tumor regressions in both BRAFV600E mutant cell derived CRC xenograft models, including HT29, Colo205, WiDr, as well as two primary human CRC xenograft models. In particular, BGB-283 shows compelling efficacy and potent inhibition of EGFR/MAPK signaling in WiDr xenograft model where EGFR reactivation occurs upon B-RAF inhibition. These findings support BGB-283 as a potent antitumor drug candidate with clinical potential for treating CRC harboring B-RAFV600E mutation. Citation Format: Zhiyu Tang, Xi Yuan, Rong Du, Shing-Hu Cheung, Guoliang Zhang, Jing Wei, Yuan Zhao, Yingcai Feng, Yi Zhang, Yunguang Du, Xiaoxia Hu, Wenfeng Gong, Yong Liu, Yajuan Gao, Rui Hao, Jiafu Ji, Lianhai Zhang, Shuangxi Li, David Sutton, Min Wei, Changyou Zhou, Lai Wang, Lusong Luo. BGB-283, a novel RAF kinase and EGFR dual inhibitor, displays potent antitumor activity in B-RAF mutated colorectal cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4692. doi:10.1158/1538-7445.AM2015-4692