Role of B-Raf(V600E) in differentiated thyroid cancer and preclinical validation of compounds against B-Raf(V600E).
Role of B-Raf(V600E) in differentiated thyroid cancer and preclinical validation of compounds against B-Raf(V600E).
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DOI：
10.1016/j.bbcan.2009.01.003
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发表时间：
2009-04
影响因子：
11.2
通讯作者：
Parangi, Sareh
中科院分区：
文献类型：
--
作者：
Nucera, Carmelo;Goldfarb, Melanie;Hodin, Richard;Parangi, Sareh
关键词：
B-RafV 600 E是一种致癌蛋白激酶，是甲状腺乳头状癌（PTC）中最常见的基因改变。PTC占所有甲状腺癌的80-90%，在过去五年中，已发表了200多篇关于“B-RafV 600 E与甲状腺癌”之间关系的手稿。B-RafV 600 E基因上由颠换点突变（在氨基酸残基-600处的缬氨酸至谷氨酸取代，V600 E）产生，并导致促分裂原活化蛋白激酶（MAPK）信号传导途径的过度活化。MAPK通路对于将由细胞表面受体和胞质信号传导元件产生的增殖信号传递到细胞核是必需的。在包括甲状腺癌在内的许多癌症中，B-RafV 600 E似乎在细胞增殖、存活和去分化中起着至关重要的作用。在甲状腺癌中，V600 E突变在PTC的侵袭性亚型中更频繁地发生，并且在存在甲状腺外延伸和/或淋巴结转移的疾病晚期的个体中更频繁地发生。B-RafV 600 E被认为是PTC（>1 cm）和微小PTC（≤1 cm）中侵袭性疾病的标志物，有趣的是，它与I-131亲和力丧失和PTC复发相关。尽管甲状腺癌患者的治疗通常是成功的，并且大多数患者都是无病的，但迄今为止，对于具有侵袭性、非放射性碘敏感性肿瘤或转移性疾病的患者没有有效的治疗方法。本文就B-RafV 600 E与PTC的关系以及目前正在研究的治疗B-RafV 600 E阳性PTC的非选择性和选择性药物进行综述。
B-RafV600E, an oncogenic protein kinase, is the most frequent genetic alteration in papillary thyroid carcinomas (PTC). PTC represents 80–90% of all thyroid cancers and over the past five years, more than 200 manuscripts have been published about the relationship between “B-RafV600E and thyroid cancer”. B-RafV600E genetically arises from a transversion point mutation (valine-to-glutamate substitution at amino acid residue-600, V600E) and leads to over activation of the mitogen-activated protein kinases (MAPK) signalling pathway. The MAPK pathway is essential for transmitting proliferation signals generated by cell surface receptors and cytoplasmic signaling elements to the nucleus. In many cancers, including thyroid cancer, B-RafV600E appears to play a crucial role in cell proliferation, survival and de-differentiation. In thyroid cancer, the V600E mutation occurs with greater frequently in aggressive subtypes of PTC, and in individuals that present at advanced stages of disease with extra-thyroidal extension and/or lymph node metastases. B-RafV600E is considered a marker of aggressive disease in both PTC (>1 cm) and micro-PTC (≤1 cm), and interestingly, is associated with both loss of I-131 avidity and PTC recurrence. Though treatment of patients with thyroid cancer is usually successful and most patients are rendered disease-free, to date there are no effective therapies for patients with invasive, non-radioiodine sensitive tumors or metastatic disease. In this article we will review the relation between B-RafV600E and PTC, as well as both non-selective and selective pharmacological agents currently under investigation for treatment of B-RafV600E positive PTC.
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