KRAS or BRAF mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancer
KRAS or BRAF mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancer
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DOI：
10.1038/sj.bjc.6604783
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发表时间：
2008-12-09
影响因子：
8.8
通讯作者：
Miyazaki, K.
中科院分区：
文献类型：
--
作者：
Nakayama, N.;Nakayama, K.;Miyazaki, K.
本研究检查了 58 例卵巢癌中与细胞外信号调节蛋白激酶 (ERK) 激活相关的 KRAS 和 BRAF 突变状态，以阐明 KRAS/BRAF 突变的临床病理学和预后意义。在 58 例卵巢癌中，有 12 例 (20.6%) 发现了 KRAS 或 BRAF 体细胞突变。传统浆液性高级别癌中KRAS/BRAF突变的频率（4.0%：1/25）显着低于其他组织学类型（32.3%：10/31）。 45 例卵巢癌中有 18 例 (38.2%) 发现磷酸化 ERK1/2 (p-ERK1/2) 表达。 KRAS/BRAF 突变与国际妇产科联合会 (FIGO) I、II 期 (P < 0.001) 和 p-ERK1/2 (P < 0.001) 显着相关。在接受铂类和紫杉烷类化疗的卵巢癌患者中，KRAS/BRAF 突变或 p-ERK1/2 表达与总生存率之间没有显着相关性（分别为 P = 0.2460、P = 0.9339）。接下来，为了阐明 ERK1/2 激活在携带 KRAS 或 BRAF 突变的卵巢癌中的作用，我们使用 CI-1040 灭活卵巢癌细胞中的 ERK1/2。 CI-1040 是一种选择性抑制 MAP 激酶激酶 (MEK)（ERK1/2 的上游调节因子）的化合物，从而防止 ERK1/2 激活。与含有野生型序列的卵巢癌细胞相比，在 KRAS 或 BRAF 突变的 CI-1040 处理的癌细胞中观察到了严重的生长抑制和细胞凋亡。这在体外和体内研究中都很明显。这项研究的结果表明，激活的 ERK1/2 通路对于具有 KRAS 或 BRAF 突变的卵巢癌的肿瘤生长和生存至关重要。此外，他们认为 CI-1040 诱导的表型取决于卵巢癌中 KRAS 和 BRAF 的突变状态。因此，具有KRAS或BRAF突变的卵巢癌患者可能受益于CI-1040治疗。
This study examined the status of KRAS and BRAF mutations, in relation to extracellular signal-regulated protein kinase (ERK) activation in 58 ovarian carcinomas to clarify the clinicopathological and prognostic significance of KRAS/BRAF mutations. Somatic mutations of either KRAS or BRAF were identified in 12 (20.6%) out of 58 ovarian carcinomas. The frequency of KRAS/BRAF mutations in conventional serous high-grade carcinomas (4.0% : 1/25) was significantly lower than that in the other histological type (32.3% : 10/31). Phosphorylated ERK1/2 (p-ERK1/2) expression was identified in 18 (38.2%) out of 45 ovarian carcinomas. KRAS/BRAF mutation was significantly correlated with International Federation of Gynecology and Obstetrics (FIGO) stage I, II (P < 0.001), and p-ERK1/2 (P < 0.001). No significant correlations between KRAS/BRAF mutations or p-ERK1/2 expression and overall survival were found in patients with ovarian carcinoma treated with platinum and taxane chemotherapy (P = 0.2460, P = 0.9339, respectively). Next, to clarify the roles of ERK1/2 activation in ovarian cancers harbouring KRAS or BRAF mutations, we inactivated ERK1/2 in ovarian cancer cells using CI-1040. CI-1040 is a compound that selectively inhibits MAP kinase kinase (MEK), an upstream regulator of ERK1/2, and thus prevents ERK1/2 activation. Profound growth inhibition and apoptosis were observed in CI-1040-treated cancer cells with mutations in either KRAS or BRAF in comparison with the ovarian cancer cells containing wild-type sequences. This was evident in both in vitro and in vivo studies. The findings in this study indicate that an activated ERK1/2 pathway is critical to tumour growth and survival of ovarian cancers with KRAS or BRAF mutations. Furthermore, they suggest that the CI-1040-induced phenotypes depend on the mutational status of KRAS and BRAF in ovarian cancers. Therefore, ovarian cancer patients with KRAS or BRAF mutations may benefit from CI-1040 treatment.