达布拉芬尼
癌症研究
V600E型
突变
MEK抑制剂
MAPK/ERK通路
曲美替尼
结直肠癌
医学
黑色素瘤
生物
威罗菲尼
癌症
内科学
信号转导
基因
遗传学
转移性黑色素瘤
作者
Yuki Shimizu,Kohei Maruyama,Mai Suzuki,Hiroshi Kawachi,Siew‐Kee Low,Tomoko Oh‐hara,Kengo Takeuchi,Naoya Fujita,Satoshi Nagayama,Ryohei Katayama
出处
期刊:Cancer Letters
[Elsevier]
日期:2022-06-17
卷期号:543: 215799-215799
被引量:5
标识
DOI:10.1016/j.canlet.2022.215799
摘要
Neuroendocrine carcinomas (NECs), a poorly differentiated subtype of neuroendocrine neoplasms, are aggressive and have a poor prognosis. Colorectal neuroendocrine carcinomas (CRC-NECs) are observed in about 0.6% of all patients with CRC. Interestingly, patients with CRC-NECs show higher frequencies of BRAF mutation than typical CRC. BRAF V600E mutation-positive CRC-NECs were shown to be sensitive to BRAF inhibitors and now are treated by BRAF inhibitors. Similar to the other BRAF V600E mutated cancers, resistances against BRAF inhibitors have been observed, but the resistance mechanisms are still unclear. In this study, we established BRAF V600E mutated CRC-NEC cell line directly from surgical specimens and experimentally obtained BRAF inhibitor dabrafenib resistant cell lines. The resistant cells are revealed to express at least three types of BRAF splicing variants harboring V600E-mutation, and contribute to RAF/MEK/ERK pathway activation. In these cells, MEK and ERK inhibitors but not dabrafenib significantly suppressed cell growth and survival. Thus, in BRAF V600E mutation-positive CRC-NECs, BRAF splicing variants activate the RAF/MEK/ERK pathway and contribute to acquire BRAF inhibitor resistance. Hence, MEK or ERK are potential therapeutic targets to overcome BRAF resistance.
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