A tightly controlled Src-YAP signaling axis determines therapeutic response to dasatinib in renal cell carcinoma.
A tightly controlled Src-YAP signaling axis determines therapeutic response to dasatinib in renal cell carcinoma.
复制标题
严格控制的 Src-YAP 信号轴决定肾细胞癌达沙替尼的治疗反应
作者：
Sun J;Wang X;Tang B;Liu H;Zhang M;Wang Y;Ping F;Ding J;Shen A;Geng M
在过去的十年中，针对 VEGF/VEGFR 和 mTOR 通路的治疗已成为肾细胞癌 (RCC) 患者临床管理的标准治疗方法。尽管前景广阔，但这些靶向药物仅获得了有限的临床益处，并且无进展生存期延长有限。因此，应引入替代的合理适用的治疗方法来改善肾细胞癌患者的临床结局。方法：筛选 FDA 批准的激酶抑制剂，评估其抑制 RCC 细胞增殖的能力。然后，通过基因表达阵列、RNAi、激酶谱和救援验证来鉴定所选药物的下游效应子、治疗靶点和信号通路。最后，在基于细胞系的异种移植模型和患者来源的异种移植模型中评估了该药物的体内有效性。结果：在这项研究中，我们发现达沙替尼是一种有效的药物，可以在体外损害肾细胞癌细胞的活力，并在体内减少肿瘤的生长。从机制上讲，我们提高了对 YAP 通过 Src-JNK-LIMD1-LATS 信号级联在 RCC 细胞中作为达沙替尼诱导的抗增殖的关键效应器的精确机制作用的理解。同时，我们的结果表明，p-YAP 的改变与达沙替尼在敏感 RCC 模型中引起的生长抑制密切相关。结论：我们的研究结果表明，达沙替尼可能作为治疗 Src-YAP 信号轴过度激活的 RCC 患者亚组的有力候选药物，并且 p-YAP 的改变可以作为达沙替尼在 RCC 中的功能反应生物标志物。
Over the past decade, therapies targeting the VEGF/VEGFR and mTOR pathways have served as the standard of care for the clinical management of renal cell carcinoma (RCC) patients. Albeit promising, these targeted drugs have attained only modest clinical benefits with limited prolonged progression-free survival. Therefore, alternative reasonable and applicable therapeutic approaches should be introduced to improve the clinical outcome of RCC patients. Methods: FDA approved kinase inhibitors were screened to evaluate their abilities to suppress the proliferation of RCC cells. Then, the downstream effector, therapeutic target and signaling pathway of the selected drug were identified by gene expression array, RNAi, kinase profile and rescue verification. Finally, the in vivo effectiveness of the drug was assessed in cell line-based xenograft models and patient-derived xenograft models. Results: In this study, we discovered that dasatinib is a potent agent that can impair RCC cell viability in vitro and decrease tumor growth in vivo. Mechanistically, we improved the understanding of the precise mechanistic role of YAP as a pivotal effector of dasatinib-induced anti-proliferation through Src-JNK-LIMD1-LATS signaling cascade in RCC cells. Meanwhile, our results indicated that the alteration of p-YAP is closely correlated to the growth inhibition caused by dasatinib in sensitive RCC models. Conclusion: Our findings provide evidence that dasatinib may serve as a powerful drug candidate to treat subgroups of RCC patients with hyper-activated Src-YAP signaling axis, and the alteration of p-YAP could serve as a functional response biomarker of dasatinib in RCC.
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影响因子：
64.5
作者：
Rosenbluh J;Nijhawan D;Cox AG;Li X;Neal JT;Schafer EJ;Zack TI;Wang X;Tsherniak A;Schinzel AC;Shao DD;Schumacher SE;Weir BA;Vazquez F;Cowley GS;Root DE;Mesirov JP;Beroukhim R;Kuo CJ;Goessling W;Hahn WC
通讯作者：
Hahn WC
影响因子：
7.3
作者：
Bean GR;Ganesan YT;Dong Y;Takeda S;Liu H;Chan PM;Huang Y;Chodosh LA;Zambetti GP;Hsieh JJ;Cheng EH
通讯作者：
Cheng EH
DOI：
10.1083/jcb.201501025
发表时间：
2015-08-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kim NG;Gumbiner BM
通讯作者：
Gumbiner BM
影响因子：
45.3
作者：
Escudier, Bernard;Eisen, Tim;Bukowski, Ronald M.
通讯作者：
Bukowski, Ronald M.
影响因子：
168.9
作者：
Escudier, Bernard;Pluzanska, Anna;Moore, Nicola
通讯作者：
Moore, Nicola