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AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status
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 BRA...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988692/ https://www.ncbi.nlm.nih.gov/pubmed/29755114 http://dx.doi.org/10.1038/s41416-018-0086-x |
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author | Ma, Rui Xu, Ling Qu, Xiujuan Che, Xiaofang Zhang, Ye Fan, Yibo Li, Ce Guo, Tianshu Hou, Kezuo Hu, Xuejun Drew, Lisa Shen, Minhui Cheung, Tony Liu, Yunpeng |
author_facet | Ma, Rui Xu, Ling Qu, Xiujuan Che, Xiaofang Zhang, Ye Fan, Yibo Li, Ce Guo, Tianshu Hou, Kezuo Hu, Xuejun Drew, Lisa Shen, Minhui Cheung, Tony Liu, Yunpeng |
author_sort | Ma, Rui |
collection | PubMed |
description | 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(50) values of 79 nM and 38 nM, respectively. By suppressing ERK phosphorylation, AZ304 effectively inhibited a panel of human cancer cell lines with different BRAF and RAS genetic statuses. In selected colorectal cancer cell lines, AZ304 significantly inhibited cell growth in vitro and in vivo, regardless of BRAF genetic status. In addition, the EGFR inhibitor Cetuximab enhanced the potency of AZ304 independently of BRAF mutational status. CONCLUSIONS: The BRAF inhibitor AZ304 has broad spectrum antitumour activity, which is significantly enhanced by combination with Cetuximab in colorectal cancers in vitro and in vivo. |
format | Online Article Text |
id | pubmed-5988692 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59886922019-05-29 AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status Ma, Rui Xu, Ling Qu, Xiujuan Che, Xiaofang Zhang, Ye Fan, Yibo Li, Ce Guo, Tianshu Hou, Kezuo Hu, Xuejun Drew, Lisa Shen, Minhui Cheung, Tony Liu, Yunpeng Br J Cancer Article 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(50) values of 79 nM and 38 nM, respectively. By suppressing ERK phosphorylation, AZ304 effectively inhibited a panel of human cancer cell lines with different BRAF and RAS genetic statuses. In selected colorectal cancer cell lines, AZ304 significantly inhibited cell growth in vitro and in vivo, regardless of BRAF genetic status. In addition, the EGFR inhibitor Cetuximab enhanced the potency of AZ304 independently of BRAF mutational status. CONCLUSIONS: The BRAF inhibitor AZ304 has broad spectrum antitumour activity, which is significantly enhanced by combination with Cetuximab in colorectal cancers in vitro and in vivo. Nature Publishing Group UK 2018-05-14 2018-05-29 /pmc/articles/PMC5988692/ /pubmed/29755114 http://dx.doi.org/10.1038/s41416-018-0086-x Text en © Cancer Research UK 2018 https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Ma, Rui Xu, Ling Qu, Xiujuan Che, Xiaofang Zhang, Ye Fan, Yibo Li, Ce Guo, Tianshu Hou, Kezuo Hu, Xuejun Drew, Lisa Shen, Minhui Cheung, Tony Liu, Yunpeng AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status |
title | AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status |
title_full | AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status |
title_fullStr | AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status |
title_full_unstemmed | AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status |
title_short | AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status |
title_sort | az304, a novel dual braf inhibitor, exerts anti-tumour effects in colorectal cancer independently of braf genetic status |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988692/ https://www.ncbi.nlm.nih.gov/pubmed/29755114 http://dx.doi.org/10.1038/s41416-018-0086-x |
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