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|Title:||Effect of FAK inhibitor VS-6063 (defactinib) on docetaxel efficacy in prostate cancer|
|Citation:||The Prostate, 2018; 78(4):308-317|
|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.|
|Appears in Collections:||Medicine publications|
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