Kiga Masaki, Nakayama Ayako, Shikata Yuki, Sasazawa Yukiko, Murakami Ryo, Nakanishi Toshiyuki, Tashiro Etsu, Imoto Masaya
1] Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan [2] Shinagawa R&D Center, Daiichi Sankyo Co. Ltd, Tokyo, Japan.
Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
Sci Rep. 2015 Feb 2;5:8155. doi: 10.1038/srep08155.
Although clinical studies have evaluated several MEK1/2 inhibitors, it is unlikely that MEK1/2 inhibitors will be studied clinically. BRAF mutations have been proposed as a responder marker of MEK1/2 inhibitors in a preclinical study. However, current clinical approaches focusing on BRAF mutations have shown only moderate sensitivity of MEK1/2 inhibitors. This has led to insufficient support for their promoted clinical adoption. Further characterization of tumors sensitive to MEK inhibitors holds great promise for optimizing drug therapy for patients with these tumors. Here, we report that β-catenin mutations accelerate apoptosis induced by MEK1/2 inhibitor. SMK-17, a selective MEK1/2 inhibitor, induced apoptosis in tumor cell lines harboring β-catenin mutations at its effective concentration. To confirm that β-catenin mutations and mutant β-catenin-mediated TCF7L2 (also known as TCF4) transcriptional activity is a predictive marker of MEK inhibitors, we evaluated the effects of dominant-negative TCF7L2 and of active, mutated β-catenin on apoptosis induced by MEK inhibitor. Indeed, dominant-negative TCF7L2 reduced apoptosis induced by MEK inhibitor, whereas active, mutated β-catenin accelerated it. Our findings show that β-catenin mutations are an important responder biomarker for MEK1/2 inhibitors.
尽管临床研究已经评估了几种MEK1/2抑制剂，但MEK1/2抑制剂不太可能再进行临床研究。在一项临床前研究中，BRAF突变被认为是MEK1/2抑制剂的反应标志物。然而，目前聚焦于BRAF突变的临床方法显示MEK1/2抑制剂的敏感性仅为中等。这导致其临床应用缺乏足够的支持。进一步明确对MEK抑制剂敏感的肿瘤特征，有望为这些肿瘤患者优化药物治疗。在此，我们报告β-连环蛋白突变会加速MEK1/2抑制剂诱导的细胞凋亡。选择性MEK1/2抑制剂SMK-17在其有效浓度下可诱导携带β-连环蛋白突变的肿瘤细胞系发生凋亡。为了证实β-连环蛋白突变以及突变型β-连环蛋白介导的TCF7L2（也称为TCF4）转录活性是MEK抑制剂的预测标志物，我们评估了显性负性TCF7L2以及活性突变型β-连环蛋白对MEK抑制剂诱导的细胞凋亡的影响。事实上，显性负性TCF7L2可减少MEK抑制剂诱导的细胞凋亡，而活性突变型β-连环蛋白则会加速细胞凋亡。我们的研究结果表明，β-连环蛋白突变是MEK1/2抑制剂的重要反应生物标志物。
