Effect of FAK inhibitor VS-6063 (defactinib) on docetaxel efficacy in prostate cancer
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.
|ISBN||1097-0045 (Electronic) 0270-4137 (Linking)|
|Authors||Lin, H. M.; Lee, B. Y.; Castillo, L.; Spielman, C.; Grogan, J.; Yeung, N. K.; Kench, J. G.; Stricker, P. D.; Haynes, A. M.; Centenera, M. M.; Butler, L. M.; Shreeve, S. M.; Horvath, L. G.; Daly, R. J.|
|Responsible Garvan Author|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/29314097|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/14659|