The RET proto-oncogene has been well-studied. RET is involved in many different physiological and developmental functions. When altered, RET mutations influence disease in a variety of organ systems from Hirschsprung's disease and multiple endocrine neoplasia 2 (MEN2) to papillary thyroid carcinoma (PTC) and non-small cell lung cancer (NSCLC). Changes in RET expression have been discovered in 30-70% of invasive breast cancers and 50-60% of pancreatic ductal adenocarcinomas in addition to colorectal adenocarcinoma, melanoma, small cell lung cancer, neuroblastoma, and small intestine neuroendocrine tumors. RET mutations have been associated with tumor proliferation, invasion, and migration. RET fusions or rearrangements are somatic juxtapositions of 5' sequences from other genes with 3' RET sequences encoding tyrosine kinase. RET rearrangements occur in approximately 2.5-73% of sporadic PTC and 1-3% of NSCLC patients. The most common RET fusions are CDCC6-RET and NCOA4-RET in PTC and KIF5B-RET in NSCLC. Tyrosine kinase inhibitors are drugs that target kinases such as RET in RET-driven (RET-mutation or RET-fusion-positive) disease. Multikinase inhibitors (MKI) target various kinases and other receptors. Several MKIs are FDA-approved for cancer therapy (sunitinib, sorafenib, vandetanib, cabozantinib, regorafenib, ponatinib, lenvatinib, alectinib) and non-oncologic disease (nintedanib). Selective RET inhibitor drugs LOXO-292 (selpercatinib) and BLU-667 (pralsetinib) are also undergoing phase I/II and I clinical trials, respectively, with preliminary results demonstrating partial response and low incidence of serious adverse events. RET fusions provide a viable therapeutic target for oncologic treatment, and further study is warranted into the prevalence and pathogenesis of RET fusions as well as development of current and new tyrosine kinase inhibitors.

中文翻译：

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实体瘤中的RET融合。

RET原癌基因已被充分研究。RET参与许多不同的生理和发育功能。改变后，RET突变会影响多种器官系统的疾病，从赫氏弹簧病和多发性内分泌肿瘤2（MEN2）到甲状腺乳头状癌（PTC）和非小细胞肺癌（NSCLC）。除了大肠腺癌，黑素瘤，小细胞肺癌，神经母细胞瘤和小肠神经内分泌肿瘤外，在30-70％的浸润性乳腺癌和50-60％的胰腺导管腺癌中发现了RET表达的变化。RET突变与肿瘤的增殖，侵袭和迁移有关。RET融合或重排是来自其他基因的5'序列与编码酪氨酸激酶的3'RET序列的体细胞并列。RET重排发生在约2.5-73％的散发PTC和1-3％的NSCLC患者中。最常见的RET融合是PTC中的CDCC6-RET和NCOA4-RET，以及NSCLC中的KIF5B-RET。酪氨酸激酶抑制剂是在RET驱动（RET突变或RET融合阳性）疾病中靶向RET等激酶的药物。多激酶抑制剂（MKI）靶向多种激酶和其他受体。几种MKI已获得FDA批准用于癌症治疗（舒尼替尼，索拉非尼，vandetanib，cabozantinib，regorafenib，ponatinib，lenvatinib，alectinib）和非肿瘤性疾病（nintedanib）。选择性RET抑制剂药物LOXO-292（selpercatinib）和BLU-667（pralsetinib）也在分别进行I / II和I期临床试验，初步结果表明部分应答和严重不良事件的发生率较低。