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

British Journal of Cancer
Rui MaYunpeng Liu

Abstract

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. 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. AZ304 exerted potent inhibitory effects on both wild type and V600E mutant forms of the serine/threonine-protein kinase BRAF, with IC50 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. The BRAF inhibitor AZ304 has broad spectrum antitumour activity, which is significantly e...Continue Reading

References

May 1, 2004·The Journal of Cell Biology·Carolyn N WrobelJoan S Brugge
Nov 13, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Federica Di NicolantonioAlberto Bardelli
May 19, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Beatriz M CarrenoGerald P Linette
Jun 7, 2011·The New England Journal of Medicine·Paul B ChapmanUNKNOWN BRIM-3 Study Group
Oct 13, 2012·Nature Reviews. Drug Discovery·Gideon BollagPeter Hirth
Dec 20, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Muling MaoScott Kopetz
Feb 13, 2013·Journal of Medicinal Chemistry·Melissa M VasbinderMinwei Ye
Apr 2, 2013·The Journal of Clinical Investigation·Ethan V AbelAndrew E Aplin
Dec 3, 2013·Biochemical Pharmacology·Amanda D Bucheit, Michael A Davies
Jan 23, 2014·Current Cancer Drug Targets·Md Atiqur RahmanAlfred King-yin Lam
Mar 4, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Alexander M Menzies, Georgina V Long
Apr 29, 2014·Cancer Discovery·David J KonieczkowskiLevi A Garraway
Oct 21, 2014·The Journal of Clinical Investigation·Niuscha YaktapourRobert Zeiser
Feb 13, 2015·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Filippo PietrantonioSandro Barni
Aug 20, 2015·The New England Journal of Medicine·David M HymanJosé Baselga
Dec 1, 2015·Pharmacogenomics·Armando OrlandiFilippo Pietrantonio
Jun 25, 2016·The Cancer Journal·Krittiya Korphaisarn, Scott Kopetz
Dec 15, 2016·Biochemical and Biophysical Research Communications·Ikuko NagasawaAkihiro Tomida
Jan 27, 2018·Cell Biochemistry and Function·Rong YuYili Teng

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Citations

May 10, 2020·Journal of Experimental & Clinical Cancer Research : CR·Wanxia FangYunpeng Liu
Jun 13, 2020·Frontiers in Oncology·Chaoxu ZhangXiujuan Qu
May 17, 2021·Seminars in Cancer Biology·Rahim UllahLixin Wan

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Methods Mentioned

BETA
AlphaScreen
ELISA
Assay
light microscopy
electrophoresis
xenograft
xenografts

Software Mentioned

GraphPad Prism
AlphaScreen

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