Targeting MET Amplification as a New Oncogenic Driver.
Targeting MET Amplification as a New Oncogenic Driver.
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DOI：
10.3390/cancers6031540
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发表时间：
2014-07-22
期刊：
影响因子：
5.2
通讯作者：
Nishio K
中科院分区：
文献类型：
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作者：
Kawakami H;Okamoto I;Okamoto W;Tanizaki J;Nakagawa K;Nishio K
某些基因定义的癌症的增殖和存活依赖于单一过度活跃的癌基因，这种现象被称为“癌基因成瘾”。选择性针对此类“驱动癌基因”的新一代药物在适当的基因定义患者中表现出比传统化疗更高的临床疗效。 MET 是一种编码受体酪氨酸激酶的原癌基因，由于包括基因扩增、多体性和基因突变在内的各种遗传改变，MET 信号传导的异常激活发生在晚期癌症的子集中。我们的临床前研究表明，使用小分子 MET 抑制剂克唑替尼或针对 MET mRNA 的 RNA 干扰抑制 MET 信号传导，可在体内和体外对 MET 扩增的癌细胞系产生显着的抗肿瘤作用。此外，MET 扩增呈阳性的非小细胞肺癌或胃癌患者对克唑替尼表现出明显的临床反应。因此，不断积累的临床前和临床证据表明，MET 扩增是一种“致癌驱动因素”，因此是有效的治疗目标。然而，MET 扩增的患病率尚未完全确定，部分原因可能是评估基因扩增存在困难。在这篇综述中，我们提供了在癌症治疗中针对这种基因改变的基本原理。
Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as “oncogene addiction”. A new generation of drugs that selectively target such “driver oncogenes” manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an “oncogenic driver” and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy.
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影响因子：
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作者：
Kawakami H;Okamoto I;Arao T;Okamoto W;Matsumoto K;Taniguchi H;Kuwata K;Yamaguchi H;Nishio K;Nakagawa K;Yamada Y
通讯作者：
Yamada Y
一种新型的SND1-BRAF融合通过[校正] MAPK激活在GTL16细胞中对C-MET抑制剂PF-04217903的抗性。
影响因子：
3.7
作者：
Lee NV;Lira ME;Pavlicek A;Ye J;Buckman D;Bagrodia S;Srinivasa SP;Zhao Y;Aparicio S;Rejto PA;Christensen JG;Ching KA
通讯作者：
Ching KA
影响因子：
45.3
作者：
Chi, Andrew S.;Batchelor, Tracy T.;Iafrate, A. John
通讯作者：
Iafrate, A. John
DOI：
10.1158/1078-0432.ccr-10-0851
发表时间：
2010-11-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Camidge DR;Kono SA;Flacco A;Tan AC;Doebele RC;Zhou Q;Crino L;Franklin WA;Varella-Garcia M
通讯作者：
Varella-Garcia M
影响因子：
45.3
作者：
Choueiri, Toni K.;Vaishampayan, Ulka;Srinivasan, Ramaprasad
通讯作者：
Srinivasan, Ramaprasad