MEK Inhibitor for Gastric Cancer with MEK1 Gene Mutations
MEK Inhibitor for Gastric Cancer with MEK1 Gene Mutations
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DOI：
10.1158/1535-7163.mct-14-0429
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发表时间：
2014-12-01
影响因子：
5.7
通讯作者：
Nishio, Kazuto
中科院分区：
文献类型：
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作者：
Sogabe, Shunsuke;Togashi, Yosuke;Nishio, Kazuto
不能切除的晚期或复发胃癌患者的预后仍然很差。需要鉴定具有与表皮生长因子受体基因突变相似的影响的其他癌基因，癌细胞的生长依赖于表皮生长因子受体基因突变。在这项研究中，我们评估了敏感性MEK抑制剂（GSK 1120212和PD 0325901）在几个胃癌细胞系在体外，发现三个低分化胃癌细胞系是高敏感的抑制剂。对这三种细胞系的序列分析显示，一种细胞系具有新的MEK 1突变，而另外两种细胞系先前分别报告了KRAS和MEK 1突变;其他耐药细胞系的基因状态均为野生型。使用MEK 1表达载体的实验表明，MEK 1突变诱导ERK 1/2磷酸化，并具有转化潜力，增强致瘤性。MEK抑制剂显著降低了ERK 1/2的磷酸化，并在MEK 1突变的细胞系中诱导凋亡。在体内，抑制剂也显著降低了肿瘤生长。46例胃癌临床样本中有1例存在MEK 1突变;该肿瘤的组织学分化较差。考虑到癌细胞对活性MEK 1突变的依赖性，具有这种致癌性MEK 1突变的胃癌可能适合使用MEK抑制剂进行靶向治疗。（C）2014年AACR。
The prognosis for patients with unresectable advanced or recurrent gastric cancer remains poor. The identification of additional oncogenes with influences similar to those of epidermal growth factor receptor gene mutations, upon which the growth of cancer cells is dependent, is needed. In this study, we evaluated sensitivity to MEK inhibitors (GSK1120212 and PD0325901) in several gastric cancer cell lines in vitro and found three poorly differentiated gastric cancer cell lines that were hypersensitive to the inhibitors. The sequence analyses in these three cell lines revealed that one cell line had a novel MEK1 mutation, while the other two had previously reported KRAS and MEK1 mutations, respectively; the gene statuses of the other resistant cell lines were all wild-type. Experiments using MEK1 expression vectors demonstrated that the MEK1 mutations induced the phosphorylation of ERK1/2 and had a transforming potential, enhancing the tumorigenicity. The MEK inhibitor dramatically reduced the phosphorylation of ERK1/2 and induced apoptosis in the cell lines with MEK1 mutations. In vivo, tumor growth was also dramatically decreased by an inhibitor. One of the 46 gastric cancer clinical samples that were examined had a MEK1 mutation; this tumor had a poorly differentiated histology. Considering the addiction of cancer cells to active MEK1 mutations for proliferation, gastric cancer with such oncogenic MEK1 mutations might be suitable for targeted therapy with MEK inhibitors. (C)2014 AACR.