Targeting RET Receptor Tyrosine Kinase Activation in Cancer
Targeting RET Receptor Tyrosine Kinase Activation in Cancer
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DOI：
10.1158/1078-0432.ccr-09-0786
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发表时间：
2010-12-15
影响因子：
11.5
通讯作者：
Shah, Manisha H.
中科院分区：
文献类型：
--
作者：
Phay, John E.;Shah, Manisha H.
在配体结合诱导二聚化后，RET受体酪氨酸激酶激活多个信号转导途径。组成性激活突变和染色体重排分别是大量甲状腺髓样癌（MTC）和甲状腺乳头状癌（PTC）的主要致癌事件。当RET中的特定生殖系突变被早期识别时，可以定时进行预防性甲状腺切除术，以去除患有多发性内分泌瘤2（MEN 2）综合征的患者中的风险组织，否则这些患者将发展MTC。进行性转移性MTC的常规治疗是有限的。小分子酪氨酸激酶抑制剂可以在纳摩尔浓度下靶向多种激酶，包括RET，并已显示出对多种恶性肿瘤的疗效。最初的临床证据表明，这些抑制剂中的几种，包括索拉非尼、凡德他尼、莫特沙尼、舒尼替尼和XL-184，可能在治疗进展性MTC中具有一些益处。虽然在这些试验中看到的初步成功似乎是适度的，但它代表了广泛转移性MTC患者治疗的重大突破。临床癌症研究; 16（24）; 5936-41。(C)2010年AACR。
After ligand binding induces dimerization, the RET receptor tyrosine kinase activates multiple signal transduction pathways. Constitutively activating mutations and chromosomal rearrangements are the primary oncogenic event in a significant number of medullary thyroid cancers (MTC) and papillary thyroid cancers (PTC), respectively. When specific germline mutations in RET are identified early, prophylactic thyroidectomy can be timed to remove at-risk tissue in patients with multiple endocrine neoplasia 2 (MEN2) syndromes who would otherwise develop MTC. Conventional therapy for progressive metastatic MTC is limited. Small-molecule tyrosine kinase inhibitors can target multiple kinases at nanomolar concentrations, including RET, and have shown efficacy against a variety of malignancies. Initial clinical evidence suggests that several of these inhibitors, including sorafenib, vandetanib, motesanib, sunitinib, and XL-184, may have some benefit in treating progressive MTC. Although initial success seen in these trials seems to be modest, it represents a major breakthrough in the treatment of patients with widespread metastatic MTC. Clin Cancer Res; 16(24); 5936-41. (C) 2010 AACR.