SMK-17, a MEK1/2-specific inhibitor, selectively induces apoptosis in β-catenin-mutated tumors.
SMK-17, a MEK1/2-specific inhibitor, selectively induces apoptosis in β-catenin-mutated tumors.
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DOI：
10.1038/srep08155
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发表时间：
2015-02-02
影响因子：
4.6
通讯作者：
Imoto M
中科院分区：
文献类型：
--
作者：
Kiga M;Nakayama A;Shikata Y;Sasazawa Y;Murakami R;Nakanishi T;Tashiro E;Imoto M
尽管临床研究已经评估了几种MEK1/2抑制剂，但MEK1/2抑制剂不太可能在临床进行研究。在一项临床前研究中，BRAF突变被认为是MEK1/2抑制剂的反应性标志物。然而，目前专注于BRAF突变的临床方法显示，MEK1/2抑制剂仅具有中等敏感性。这导致对推广临床应用的支持不足。进一步表征对MEK抑制剂敏感的肿瘤为优化这些肿瘤患者的药物治疗提供了很大的希望。在这里，我们报道β-catenin突变加速了MEK1/2抑制剂诱导的细胞凋亡。SMK-17是一种选择性MEK1/2抑制剂，在其有效浓度下可诱导含有β-catenin突变的肿瘤细胞系凋亡。为了证实β-catenin突变和突变β-catenin介导的TCF7L2（也称为TCF4）转录活性是MEK抑制剂的预测标志物，我们评估了显性阴性TCF7L2和活性突变β-catenin对MEK抑制剂诱导的细胞凋亡的影响。的确，显性阴性的TCF7L2可减少MEK抑制剂诱导的细胞凋亡，而活性突变的β-catenin可加速细胞凋亡。我们的研究结果表明β-catenin突变是MEK1/2抑制剂的重要应答生物标志物。
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.
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影响因子：
4.3
作者：
Cartlidge, Robert A.;Thomas, G. R.;McMahon, Martin
通讯作者：
McMahon, Martin
影响因子：
64.8
作者：
Dominguez-Sola, David;Ying, Carol Y.;Dalla-Favera, Riccardo
通讯作者：
Dalla-Favera, Riccardo
DOI：
10.1093/jnci/95.8.625
发表时间：
2003-04-16
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Cohen, J;Xing, MZ;Sidransky, D
通讯作者：
Sidransky, D
影响因子：
5.7
作者：
Davies, Barry R.;Logie, Armelle;Smith, Paul D.
通讯作者：
Smith, Paul D.
影响因子：
11.2
作者：
Daouti, Sherif;Wang, Huisheng;Niu, Huifeng
通讯作者：
Niu, Huifeng