AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status

AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently... www.nature.com/bjc ARTICLE Translational Therapeutics AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status 1,2 1,2 1,2 1,2 1,2 1,2 1,2 1,2 1,2 3 Rui Ma , Ling Xu , Xiujuan Qu , Xiaofang Che , Ye Zhang , Yibo Fan ,Ce Li , Tianshu Guo , Kezuo Hou , Xuejun Hu , 4 4 4 1,2 Lisa Drew , Minhui Shen , Tony Cheung and Yunpeng Liu BACKGROUND: BRAF mutation is associated with poor clinical outcome of patients with malignant tumours, and mediates resistance to chemotherapy and targeted therapy. This study aimed to determine whether V600E mutant and wild type BRAF colorectal cancers exhibit distinct sensitivities to the dual BRAF inhibitor AZ304. METHODS: Kinase activity was assessed by the AlphaScreen assay. Then, MTT assay, EdU assay, colony-formation assay and Western blot were performed to evaluate the anti-tumour effects of AZ304 in vitro. In vivo efficacy was investigated by xenograft analysis and immunohistochemistry. RESULTS: AZ304 exerted potent inhibitory effects on both wild type and V600E mutant forms of the serine/threonine-protein kinase BRAF, with IC values of 79 nM and 38 nM, respectively. By suppressing ERK phosphorylation, AZ304 effectively inhibited a panel of http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status

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Publisher
Nature Publishing Group UK
Copyright
Copyright © 2018 by Cancer Research UK
Subject
Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
ISSN
0007-0920
eISSN
1532-1827
D.O.I.
10.1038/s41416-018-0086-x
Publisher site
See Article on Publisher Site

Abstract

www.nature.com/bjc ARTICLE Translational Therapeutics AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status 1,2 1,2 1,2 1,2 1,2 1,2 1,2 1,2 1,2 3 Rui Ma , Ling Xu , Xiujuan Qu , Xiaofang Che , Ye Zhang , Yibo Fan ,Ce Li , Tianshu Guo , Kezuo Hou , Xuejun Hu , 4 4 4 1,2 Lisa Drew , Minhui Shen , Tony Cheung and Yunpeng Liu BACKGROUND: BRAF mutation is associated with poor clinical outcome of patients with malignant tumours, and mediates resistance to chemotherapy and targeted therapy. This study aimed to determine whether V600E mutant and wild type BRAF colorectal cancers exhibit distinct sensitivities to the dual BRAF inhibitor AZ304. METHODS: Kinase activity was assessed by the AlphaScreen assay. Then, MTT assay, EdU assay, colony-formation assay and Western blot were performed to evaluate the anti-tumour effects of AZ304 in vitro. In vivo efficacy was investigated by xenograft analysis and immunohistochemistry. RESULTS: AZ304 exerted potent inhibitory effects on both wild type and V600E mutant forms of the serine/threonine-protein kinase BRAF, with IC values of 79 nM and 38 nM, respectively. By suppressing ERK phosphorylation, AZ304 effectively inhibited a panel of

Journal

British Journal of CancerSpringer Journals

Published: May 14, 2018

References

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