Theranostics 2018; 8(12):3256-3267. doi:10.7150/thno.23964

Research Paper

A tightly controlled Src-YAP signaling axis determines therapeutic response to dasatinib in renal cell carcinoma

Jingya Sun1,2, Xin Wang1,2, Boyun Tang3, Hongchun Liu1,2, Minmin Zhang1,2, Yueqin Wang1,2, Fangfang Ping1,2, Jian Ding1,2✉, Aijun Shen1,2✉, Meiyu Geng1,2✉

1. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
2. University of Chinese Academy of Sciences, Beijing 100049, China;
3. Gene Company Ltd, Shanghai 200233, China.

Abstract

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.

Keywords: dasatinib, YAP, Src, renal cell carcinoma

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Sun J, Wang X, Tang B, Liu H, Zhang M, Wang Y, Ping F, Ding J, Shen A, Geng M. A tightly controlled Src-YAP signaling axis determines therapeutic response to dasatinib in renal cell carcinoma. Theranostics 2018; 8(12):3256-3267. doi:10.7150/thno.23964. Available from http://www.thno.org/v08p3256.htm