Targeting the RET Pathway in Thyroid Cancer
Targeting the RET Pathway in Thyroid Cancer
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DOI：
10.1158/1078-0432.ccr-08-2742
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发表时间：
2009-12-01
影响因子：
11.5
通讯作者：
Santoro, Massimo
中科院分区：
文献类型：
--
作者：
Wells, Samuel A., Jr.;Santoro, Massimo
RET（转染期间重排）原癌基因编码单次跨膜受体，该受体在神经嵴和泌尿生殖道衍生的细胞中表达。作为细胞表面复合物的一部分，RET 结合神经胶质源性神经营养因子 (GDNF) 配体以及 GDNF 家族 a 共受体 (GFR α)。配体诱导的激活诱导 RET 受体的二聚化和酪氨酸磷酸化，并激活下游的多个信号转导途径。激活种系 RET 突变在多发性内分泌肿瘤 (MEN) 综合征 MEN2A、MEN2B 和家族性甲状腺髓样癌 (FMTC) 的发展以及先天性异常先天性巨结肠的发展中发挥着核心作用。大约 50% 的散发性 MTC 患者具有体细胞 RET 突变，并且很大一部分甲状腺乳头状癌是由染色体倒位或易位引起的，从而激活 RET（RET/PTC 癌基因）。 RET原癌基因在癌症预防和治疗中具有重要地位。对遗传了 RET 突变等位基因（MEN2A、MEN213 或 FMTC 特征）的亲属及时进行甲状腺切除术，可以预防 MTC（这些综合征中最常见的死亡原因）。此外，最近开发的针对 RET 通路的分子疗法在晚期 MTC 患者的临床试验中显示出活性，而这种疾病目前还没有有效的治疗方法。 （临床癌症研究 2009；15(23)：7119-23）
The RET (rearranged during transfection) protooncogene encodes a single pass transmembrane receptor that is expressed in cells derived from the neural crest and the urogenital tract. As part of a cell-surface complex, RET binds glial derived neurotrophic factor (GDNF) ligands in conjunction with GDNF-family a co-receptors (GFR alpha). Ligand-induced activation induces dimerization and tyrosine phosphorylation of the RET receptor with downstream activation of several signal transduction pathways. Activating germline RET mutations play a central role in the development of the multiple endocrine neoplasia (MEN) syndromes MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC) and also in the development of the congenital abnormality Hirschsprung's disease. Approximately 50% of patients with sporadic MTC have somatic RET mutations, and a significant portion of papillary thyroid carcinomas result from chromosomal inversions or translocations, which activate RET (RET/PTC oncogenes). The RET protooncogene has a significant place in cancer prevention and treatment. Timely thyroidectomy in kindred members who have inherited a mutated RET allele, characteristic of MEN2A, MEN213, or FMTC, can prevent MTC, the most common cause of death in these syndromes. Also, recently developed molecular therapeutics that target the RET pathway have shown activity in clinical trials of patients with advanced MTC, a disease for which there has been no effective therapy. (Clin Cancer Res 2009;15(23): 7119-23)