Ahn Soomin, Brant Roz, Sharpe Alan, Dry Jonathan R, Hodgson Darren R, Kilgour Elaine, Kim Kyung, Kim Seung Tae, Park Se Hoon, Kang Won Ki, Kim Kyoung-Mee, Lee Jeeyun
Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
AstraZeneca, Oncology Innovative Medicines, Alderley Park, Macclesfield, UK.
Oncotarget. 2017 May 23;8(64):107492-107499. doi: 10.18632/oncotarget.18182. eCollection 2017 Dec 8.
MEK inhibitor (selumetinib) is a potent, orally active inhibitor of MAPK/ERK pathway. It is important to develop an accurate and robust method indicative of RAS pathway activity to stratify potential patients who can benefit from selumetinib treatment in gastric cancer (GC). First, we surveyed the sensitivity to selumetinib in a panel of 22 GC cell lines and correlated with MEK signature to selumetinib sensitivity. Next, we analyzed MEK signature via nanostring assay in two Asian cohorts using clinical samples ( = 218) and then performed a correlative analysis with MEK signature status and genotype in GC. MEK signature was predictive of response of selumetinib in GC cell lines regardless of mutation status. The proportion of high MEK signature by nanostring assay was 6.9% and the proportion of high MEK signature was significantly higher in altered group in a Korean cohort. None of altered cases belonged to high MEK signature group. MEK high signature was more prevalent in intestinal type by Lauren classification. The correlation between MEK signature, alteration and treatment response to selumetinib should be validated in prospective clinical trials.
MEK抑制剂（司美替尼）是一种有效的、口服活性的MAPK/ERK通路抑制剂。开发一种准确且可靠的方法来指示RAS通路活性，以对可能从司美替尼治疗中获益的胃癌（GC）潜在患者进行分层，这一点很重要。首先，我们在一组22种GC细胞系中检测了对司美替尼的敏感性，并将其与司美替尼敏感性的MEK特征相关联。接下来，我们通过纳米串分析在两个亚洲队列中使用临床样本（n = 218）分析了MEK特征，然后在GC中对MEK特征状态与KRAS基因型进行了相关性分析。无论KRAS突变状态如何，MEK特征均可预测司美替尼在GC细胞系中的反应。通过纳米串分析得出的高MEK特征比例为6.9%，在韩国队列的KRAS改变组中，高MEK特征比例显著更高。没有KRAS改变的病例属于高MEK特征组。根据劳伦分类，MEK高特征在肠型中更为普遍。MEK特征、KRAS改变与司美替尼治疗反应之间的相关性应在前瞻性临床试验中得到验证。
