Kinase Inhibition in Kidney Cancer

摘要 肾细胞癌的发病率呈上升趋势。美国每年发生6.5万例新病例 各州。血管内皮生长因子受体与哺乳动物雷帕霉素靶点 抑制剂是FDA批准的治疗晚期肾癌的常用药物，但会导致 总体生存时间只差几个月。此时，基因组中最容易下药的部分仍然是动态组。 通过无偏见的高通量筛查，我们已经确定并验证了一种新的治疗价值 肾细胞癌中的酪氨酸激酶2(TYK2：Janus Kinase家族的成员)，并证明它在 在mTOR抑制剂耐药中的作用。我们已经刻画了一个信令网络，其中TYK2是肯定的 调节SRC家族激酶(SFK)，并证明mTOR和SRC的双重抑制与 伊维洛莫司和达沙替尼在体内诱导肿瘤消退。根据这些结果，我们假设 抑制TYK2/SRC轴在肾癌的子集中是一种易于处理的治疗策略，我们可以定义 TYK2/SRC抑制剂反应的预测标记物，以及定义肾细胞癌及其相关基因的运动学特征 对mTOR抑制的反应将导致进一步的组合靶点。

ABSTRACT The incidence of renal cell carcinoma (RCC) is on the rise. 65,000 new cases occur annually in the United States. Vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) inhibitors are FDA approved and commonly used treatments for advanced RCC but result in increases in overall survival by only months. At this time, the most druggable portion of the genome remains the kinome. Through unbiased, high-throughput screening we have identified and validated the therapeutic value of a novel kinase in RCC, tyrosine kinase 2 (TYK2: a member of the Janus Kinase family) and demonstrate that it plays a role in mTOR inhibitor resistance. We have characterized a signaling network in which TYK2 positively regulates the SRC family kinases (SFKs) and demonstrate that dual inhibition of mTOR and SRC with everolimus and dasatinib induces tumor regression in vivo. Based on these results we hypothesize that inhibition of the TYK2/SRC axis is a tractable therapeutic strategy in a subset of RCC, that we can define predictive markers of TYK2/SRC inhibitor response, and that defining the kinomic landscape of RCC and its response to mTOR inhibition will lead to further combinatorial targets.