2. Academic Validation
  3. 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 of BRAF genetic status

  • Br J Cancer. 2018 May;118(11):1453-1463. doi: 10.1038/s41416-018-0086-x.
Rui Ma 1 2,  Ling Xu 1 2,  Xiujuan Qu 3 4,  Xiaofang Che 1 2,  Ye Zhang 1 2,  Yibo Fan 1 2,  Ce Li 1 2,  Tianshu Guo 1 2,  Kezuo Hou 1 2,  Xuejun Hu 5,  Lisa Drew 6,  Minhui Shen 6,  Tony Cheung 6,  Yunpeng Liu 7 8
Affiliations

Affiliations

  • 1 Department of Medical Oncology, The First Hospital of China Medical University, 110001, Shenyang, China.
  • 2 Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, 110001, Shenyang, China.
  • 3 Department of Medical Oncology, The First Hospital of China Medical University, 110001, Shenyang, China. xiujuanqu@yahoo.com.
  • 4 Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, 110001, Shenyang, China. xiujuanqu@yahoo.com.
  • 5 Department of Respiratory Medicine, The First Hospital of China Medical University, 110001, Shenyang, China.
  • 6 Oncology iMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA, 02451, USA.
  • 7 Department of Medical Oncology, The First Hospital of China Medical University, 110001, Shenyang, China. cmuliuyunpeng@hotmail.com.
  • 8 Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, 110001, Shenyang, China. cmuliuyunpeng@hotmail.com.
PMID: 29755114 DOI: 10.1038/s41416-018-0086-x
Abstract

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 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.

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-117273
    99.96%, Raf抑制剂
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