CLIN CANCER RES:靶向TFE3/IRS-1/PI3K/mTOR轴治疗易位肾细胞癌

2018-12-19 MedSci MedSci原创

易位肾细胞癌(tRCC)是一种罕见的肾癌亚型,与TFE3,TFEB或MITF基因融合有关,对RCC的标准治疗无反应。因此,需要寻找新的治疗靶标。CLIN CANCER RES近期发表了一篇文章研究这一问题。

易位肾细胞癌(tRCC)是一种罕见的肾癌亚型,与TFE3,TFEB或MITF基因融合有关,对RCC的标准治疗无反应。因此,需要寻找新的治疗靶标。CLIN CANCER RES近期发表了一篇文章研究这一问题。

作者建立了tRCC患者来源的异种移植模型RP-R07,作为应用二代测序和生物信息学分析进行药物开发的临床前模型。然后使用体外和体内模型评估抑制靶向信号通路的治疗效果。研究结果发现,通过RNA-seq发现SFPQ-TFE3融合的存在,并通过RT-PCR得到验证。TFE3染色质免疫沉淀联合深度测序分析发现RP-R07模型中PI3K/AKT/mTOR通路富集。miRNA芯片也发现PI3K/AKT/mTOR是RP-R07模型中的高度富集通路。与透明细胞RCC细胞相比,tRCC细胞系中磷酸-S6和磷酸-4EBP1表达更高,TFE3-tRCC模型中PI3/AKT/mTOR通路也出现上调。与单节点抑制相比,PI3K/AKT和mTOR轴的多点靶向抗增殖效果更明显。RP-R07模型中敲低TFE3导致IRS-1的表达降低并抑制细胞增殖。

文章最后认为,TFE3/IRS-1/PI3K/AKT/mTOR可能是TFE3-tRCC中的异常通路。对TFE3-tRCC患者使用双重PI3K/mTOR抑制剂具有治疗潜力。

原始出处:

Nur P. Damayanti, Justin A. Budka, et al. Therapeutic Targeting of TFE3/IRS-1/PI3K/mTOR Axis in Translocation Renal Cell Carcinoma. CLIN CANCER RES. December 2018 doi: 10.1158/1078-0432.CCR-18-0269

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