Abstract
BackgroundBRAF 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.MethodsKinase 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.ResultsAZ304 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.ConclusionsThe BRAF inhibitor AZ304 has broad spectrum antitumour activity, which is significantly enhanced by combination with Cetuximab in colorectal cancers in vitro and in vivo.
Highlights
The oncogenic BRAF mutations are found in approximately 8% of all human cancers, including 40–70% of melanoma, 36–53% of thyroid, and 5–22% of colorectal cancer (CRC) cases
The BRAF-specific inhibitors vemurafenib and dabrafenib have been approved for the treatment of melanomas harbouring the BRAF V600E mutation, but not BRAF wild type harbouring melanomas.[21]
In addition to BRAF mutations, wild type BRAF-mediated ERK activation plays a major role in tumour proliferation of uveal melanoma,[24] indicating that suppression of both mutant and wild type BRAF can improve antitumour effects
Summary
AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status. Rui Ma1,2, Ling Xu1,2, Xiujuan Qu1,2, Xiaofang Che[1,2], Ye Zhang[1,2], Yibo Fan[1,2], Ce Li1,2, Tianshu Guo[1,2], Kezuo Hou[1,2], Xuejun Hu3, Lisa Drew[4], Minhui Shen[4], Tony Cheung[4] and Yunpeng Liu[1,2]
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