2. Academic Validation
  3. Targeting of super-enhancers and mutant BRAF can suppress growth of BRAF-mutant colon cancer cells via repression of MAPK signaling pathway

Targeting of super-enhancers and mutant BRAF can suppress growth of BRAF-mutant colon cancer cells via repression of MAPK signaling pathway

  • Cancer Lett. 2017 Aug 28;402:100-109. doi: 10.1016/j.canlet.2017.05.017.
Yoshiaki Nakamura 1,  Naoko Hattori 2,  Naoko Iida 2,  Satoshi Yamashita 2,  Akiko Mori 2,  Kana Kimura 2,  Takayuki Yoshino 3,  Toshikazu Ushijima 4
Affiliations

Affiliations

  • 1 Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan; Medical Science Program, Graduate School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
  • 2 Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
  • 3 Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
  • 4 Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: tushijim@ncc.go.jp.
PMID: 28576751 DOI: 10.1016/j.canlet.2017.05.017
Abstract

Bromodomain and extra-terminal (BET) inhibitors suppress super-enhancers and show cytotoxicity against multiple types of tumors. However, early clinical trials with BET inhibitors showed severe hematopoietic toxicities, highlighting the need for sensitive tumors and rational combination strategies to enhance their therapeutic potential. Here, we identified colon cancer-specific super-enhancers that were associated with multiple oncogenic pathways, including the mitogen-activated protein kinase (MAPK) signaling pathway. Among the 14 colon Cancer cell lines tested, their sensitivity to JQ1, a BET inhibitor, was not correlated with c-Myc expression. Three of four BRafV600E-mutant cell lines were sensitive. Addition of JQ1 to vemurafenib, a specific mutant BRaf Inhibitor, suppressed cell growth by arresting cell cycle progression and inducing Apoptosis in the BRafV600E-mutant cells. Mechanistically, the feedback activation of MAPK signaling pathway by vemurafenib was repressed by JQ1. Further, the addition of JQ1 to a BRaf Inhibitor enhanced the in vivo anti-tumor effect. Thus, this study indicates the therapeutic potential of targeting of super-enhancers and mutant BRaf in patients with BRafV600E-mutant colorectal Cancer.

Keywords

BET; BRAF; Colorectal cancer; Epigenetic therapy; Super-enhancer.

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