Abstract 1230: BGB-283: a novel RAF Dimer inhibitor, displays potent antitumor activity in HCC patient derived xenograft models

Liver cancer has the third highest mortality rate among all cancers in China and hepatocellular carcinoma (HCC) is the most common type of liver cancer. The mitogen-activated protein kinase (MAPK) signaling pathway is often constitutively active in HCC. The growth of HCC requires the formation of new blood vessels. and VEGF is critical in this process. Sorafenib, a multikinase inhibitor that targets both RAF and VEGF receptor, is to date the only approved drug to treat advanced stages of HCC. Despite sorafenib extended the survival in patients with HCC, its clinical benefits remain modest and drug resistance is common. BGB283 is a second generation RAF inhibitor with unique RAF dimer and VEGFR inhibition activity. Thus, there is good rationale to test BGB-283 in HCC. In this study, we compared the in vitro and in vivo activities of BGB-283 and sorafinib in human HCC cell lines and patient derived HCC xenograft models. In the biochemical assays, BGB-283 demonstrated great potency for BRAF-V600E, BRAF-WT, CRAF(IC50 = 32, 69 and 6.5 nM, respectively) and for VEGFR family enzymes, VEGFR1, VEGFR2 and VEGFR3 (IC50 = 25, 14 and 58 nM, respectively). In the cellular assays, the anti-proliferative effect of BGB-283 and sorafinib was evaluated in several HCC cell lines. A head-to-head comparison of in vivo anti-tumor activities of BGB-283 and sorafinib were also evaluated in human primary HCC xenograft mouse models. The patient derived xenograft (PDX) HCC models were established in house using HCC patient surgical samples. Sorafinib was not active in 2 out of 7 models. Oral administration of BGB-283 resulted in significant tumor growth inhibition in all 7 models and was significantly more efficacious than sorafinib in 4 models and similar in the other 3 models. In conclusion, BGB-283 is a unique RAF dimer inhibitor with VEGFR inhibition activity. BGB-283 has also demonstrated better anti-tumor activity than sorafinib in HCC PDX models, suggesting BGB-283 could be a promising drug candidate for treating HCC patients. Citation Format: Zhiyu Tang, Yong Liu, Beibei Jiang, Yajuan Gao, Wenfeng Gong, Xing Wang, Dan Su, Fenglong Yu, Ye Liu, Min Wei, Lai Wang. BGB-283: a novel RAF Dimer inhibitor, displays potent antitumor activity in HCC patient derived xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1230.