Targeting AXL overcomes resistance to docetaxel therapy in advanced prostate cancer
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Jian-Zhong Lin1, Zeng-Jun Wang2, Wei De3, Ming Zheng2, Wei-Zhang Xu4, Hong-Fei Wu1, Alex Armstrong5 and Jia-Geng Zhu6
1Department of Urology, BenQ Medical Center, Nanjing Medical University, Nanjing, China
2Department of Urology, The First Clinical College of Nanjing Medical University, Nanjing, China
3Department of Biochemistry and Molecular biology, Nanjing Medical University, Nanjing, China
4Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing, China
5Department of Pharmacology, University of Manchester, Manchester, England
6Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
Jian-Zhong Lin, email: [email protected]
Jia-Geng Zhu, email: [email protected]
Keywords: AXL, docetaxel resistance, prostate cancer, epithelial-mesenchymal transition (EMT), ATP-binding cassette B1 (ABCB1)
Received: September 22, 2016 Accepted: March 01, 2017 Published: April 11, 2017
Resistance to docetaxel is a major clinical problem in advanced prostate cancer. The overexpression of AXL receptor tyrosine kinase (AXL) has been correlated with chemotherapeutic drug resistance. However, the role of AXL expression in docetaxel resistance in prostate cancer is yet unclear. In this study, we demonstrate that AXL is overexpressed and activated independent of Gas6 in docetaxel-resistant prostate cancer cells (PC3-DR and DU145-DR). Moreover, we show that forced overexpression of AXL in PC3 and DU145 cells is sufficient to induce resistance to docetaxel in these cell lines. Notably, genetic or pharmacologic inhibition of AXL in the resistant models suppressed cell proliferation, migration, invasion, and tumor growth, and these effects were significantly augmented when AXL inhibition was combined with docetaxel treatment. Mechanistically, we found that AXL inhibition led to reversion of the epithelial-mesenchymal transition (EMT) phenotype and decreased the expression of ATP-binding cassette B1 (ABCB1). Overall, our results identify AXL as an important mediator of docetaxel resistance in prostate cancer. We propose that AXL-targeted therapy, in combination with docetaxel, has the potential to improve the response to docetaxel therapy and reduce resistance induced by prolonged docetaxel therapy in prostate cancer.
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