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https://hdl.handle.net/2440/111573
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Type: | Journal article |
Title: | Effect of FAK inhibitor VS-6063 (defactinib) on docetaxel efficacy in prostate cancer |
Author: | Lin, H. Lee, B. Castillo, L. Spielman, C. Grogan, J. Yeung, N. Kench, J. Stricker, P. Haynes, A. Centenera, M. Butler, L. Shreeve, S. Horvath, L. Daly, R. |
Citation: | The Prostate, 2018; 78(4):308-317 |
Publisher: | Wiley |
Issue Date: | 2018 |
ISSN: | 0270-4137 1097-0045 |
Statement of Responsibility: | Hui-Ming Lin, Brian Y. Lee, Lesley Castillo, Calan Spielman, Judith Grogan, Nicole K. Yeung, James G. Kench, Phillip D. Stricker, Anne-Maree Haynes, Margaret M. Centenera, Lisa M. Butler, S. Martin Shreeve, Lisa G. Horvath, Roger J. Daly |
Abstract: | Background: Docetaxel, the standard chemotherapy for metastatic castration-resistant prostate cancer (CRPC) also enhances the survival of patients with metastatic castration-sensitive prostate cancer (CSPC) when combined with androgen-deprivation therapy. Focal Adhesion Kinase (FAK) activation is a mediator of docetaxel resistance in prostate cancer cells. The aim of this study was to investigate the effect of the second generation FAK inhibitor VS-6063 on docetaxel efficacy in pre-clinical CRPC and CSPC models. Methods: Docetaxel-resistant CRPC cells, mice with PC3 xenografts, and ex vivo cultures of patient-derived primary prostate tumors were treated with VS-6063 and/or docetaxel, or vehicle control. Cell counting, immunoblotting, and immunohistochemistry techniques were used to evaluate the treatment effects. Results: Docetaxel and VS-6063 co-treatment caused a greater decrease in the viability of docetaxel-resistant CRPC cells, and a greater inhibition in PC3 xenograft growth compared to either monotherapy. FAK expression in human primary prostate cancer was positively associated with advanced tumor stage. Patient-derived prostate tumor explants cultured with both docetaxel and VS-6063 displayed a higher percentage of apoptosis in cancer cells, than monotherapy treatment. Conclusions; Our findings suggest that co-administration of the FAK inhibitor, VS-6063, with docetaxel represents a potential therapeutic strategy to overcome docetaxel resistance in prostate cancer. |
Keywords: | Chemoresistance; defactinib; Docetaxel; focal adhesion kinase; prostate cancer; VS-6063 |
Rights: | © 2018 Wiley Periodicals, Inc. |
DOI: | 10.1002/pros.23476 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/535903 http://purl.org/au-research/grants/nhmrc/1058540 http://purl.org/au-research/grants/arc/FT130101004 |
Published version: | http://dx.doi.org/10.1002/pros.23476 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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