The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer.
The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer.
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DOI：
10.1016/j.beem.2017.04.013
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Santoro M
中科院分区：
文献类型：
--
作者：
De Falco V;Carlomagno F;Li HY;Santoro M
RET受体酪氨酸激酶（RTK）在几种人类恶性肿瘤（包括乳头状和髓样甲状腺癌、肺腺癌、结直肠癌、Spitzoid肿瘤、唾液腺癌和慢性骨髓增生性疾病）中充当个体发生驱动因子，继发于点突变、小插入/缺失和基因融合等多种遗传病变。在其他肿瘤中，包括乳腺癌和胰腺癌，RET过表达上调。因此，正在研究具有RET酪氨酸激酶抑制活性（TKI）的小分子化合物用于这些恶性肿瘤的靶向治疗。RET抑制酶活性IC 50在纳摩尔范围内的多靶向TKI已进入临床实践，注册用于治疗甲状腺髓样癌（凡德他尼、卡博替尼）、放射性碘难治性非甲状腺髓样癌（乐伐替尼、索拉非尼）或其他部位癌症（舒尼替尼、泊那替尼、瑞格非尼）。这篇综述总结了RET致癌活性的机制和新的TKI的特性，在临床前阶段，已经证明了有前途的抗RET活性。
RET receptor tyrosine kinase (RTK) acts as an ontogenetic driver in several human malignancies, including papillary and medullary thyroid carcinoma, lung adenocarcinoma, colorectal carcinoma, Spitzoid neoplasms, salivary gland carcinoma and chronic myeloproliferative disorders, secondary to as diverse genetic lesions as point-mutations, small insertions/deletions, and gene fusions. In other neoplasms, including breast and pancreatic adenocarcinoma, RET over-expression is up-regulated. Thus, small molecule compounds with RET tyrosine kinase inhibitory activity (TKIs) are being investigated for the targeted treatment of these malignancies. Multi-targeted TKIs with the RET inhibitory enzymatic activity of IC50 in the nanomolar range have entered clinical practice, registered for the treatment of medullary thyroid cancer (vandetanib, cabozantinib), radioiodine refractory non medullary thyroid cancer (lenvatinib, sorafenib) or cancers of other sites (sunitinib, ponatinib, regorafenib). This review summarizes mechanisms of RET oncogenic activity and properties of new TKIs that, at the preclinical stage, have demonstrated promising anti-RET activity.
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