文章：

重新审视RET：扩大致癌组合

RET revisited: expanding the oncogenic portfolio

原文发布日期：2014-02-24

DOI: 10.1038/nrc3680

类型: Review Article

开放获取: 否

要点：

1. The RET receptor tyrosine kinase is required for the development of neural and genitourinary tissues, but deregulation of RET activity is an important contributor to several human cancers.
2. Activating point mutations in key functional motifs cause the inherited cancer syndrome multiple endocrine neoplasia type 2. RET rearrangements that lead to constitutively active cytosolic chimeric proteins occur somatically in sporadic carcinomas of the thyroid and the lung, and they have recently been found in patients with chronic myelomonocytic leukaemia, among others.
3. Expression and activation of wild-type RET is recognized in several tumour types, where it can contribute to tumour progression by multiple mechanisms. RET activity increases tumour regional invasion and perineural spread in carcinoma of the pancreas, and it is associated with the development of resistance to endocrine therapies in breast carcinoma.
4. RET activity contributes to tumour-associated inflammation by increasing levels of pro-inflammatory cytokines and chemokines in the tumour microenvironment, thereby recruiting primary immune cells and promoting tumour growth, invasive spread and/or distant metastasis.
5. Therapeutic approaches that target RET with small-molecule kinase inhibitors have proved to be clinically valuable in medullary thyroid cancer and are being evaluated for other cancers that are associated with RET mutations or increased RET expression.
6. Although anti-RET therapeutics are an important advance in managing RET-associated malignancies, RET also has important roles in the survival and maintenance of other tissues, such as neural cell types, which might have long-term implications for extended use of these therapies.

要点翻译：

1. RET受体酪氨酸激酶是神经和泌尿生殖组织发育所必需的，但其活性失调是多种人类癌症的重要诱因。
2. 关键功能基序中的点突变激活会导致遗传性癌症综合征——2型多发性内分泌腺瘤病。导致组成性活性胞质嵌合蛋白的RET重排，发生于甲状腺和肺散发性癌的体细胞中，近期还在慢性粒-单核细胞白血病等患者中发现。
3. 野生型RET的表达和激活在多种肿瘤类型中被确认，它可通过多重机制促进肿瘤进展。RET活性会增强胰腺癌的区域浸润和神经周围扩散，并与乳腺癌内分泌治疗耐药性的产生相关。
4. RET活性通过提高肿瘤微环境中促炎细胞因子和趋化因子水平，促进肿瘤相关炎症，进而招募原发性免疫细胞，推动肿瘤生长、侵袭扩散和/或远处转移。
5. 针对RET的小分子激酶抑制剂治疗方法已在甲状腺髓样癌中显示出临床价值，目前正针对其他RET突变或高表达的癌症进行评估。
6. 尽管抗RET疗法是治疗RET相关恶性肿瘤的重要进展，但RET在神经细胞等其他组织的存活和维持中亦具有重要作用，这可能对长期应用此类疗法产生潜在影响。

英文摘要：

The RET receptor tyrosine kinase is crucial for normal development but also contributes to pathologies that reflect both the loss and the gain of RET function. Activation of RET occurs via oncogenic mutations in familial and sporadic cancers — most notably, those of the thyroid and the lung. RET has also recently been implicated in the progression of breast and pancreatic tumours, among others, which makes it an attractive target for small-molecule kinase inhibitors as therapeutics. However, the complex roles of RET in homeostasis and survival of neural lineages and in tumour-associated inflammation might also suggest potential long-term pitfalls of broadly targeting RET.

摘要翻译： 

RET受体酪氨酸激酶对正常发育至关重要，但也参与反映其功能丧失与获得相关的病理过程。RET的激活源于家族性及散发性癌症中的致癌突变——最显著的是甲状腺癌和肺癌。RET近期还被证实参与乳腺癌、胰腺癌等多种肿瘤的进展，使其成为小分子激酶抑制剂治疗的热门靶点。然而，RET在神经谱系稳态与存活以及肿瘤相关炎症中的复杂作用，也可能提示广泛抑制RET存在潜在的长期风险。

原文链接：

RET revisited: expanding the oncogenic portfolio