Docetaxel is the standard chemotherapy treatment for metastatic castration-resistant prostate cancer (CRPC). The response rate of 50% and eventual development of docetaxel-resistance highlights the need for an understanding of resistance mechanisms and the development of new therapeutic strategies. Previously we identified enhanced Focal Adhesion Kinase (FAK) activation as a mediator of docetaxel resistance, and showed that docetaxel-resistance in prostate cancer cells could be reversed by co-treatment with FAK inhibitor PF-00562271. PF-00562271 is a potent inhibitor of CYP3A, the main enzyme that metabolises docetaxel.
The second generation FAK inhibitor VS-6063 (defactinib) is a weak inhibitor of CYP3A, and thus may be a safer alternative for co-administration with docetaxel. In this study, we investigated the effect of co-administration of VS-6063 on docetaxel efficacy in prostate cancer cell lines, tumour-bearing mice, and ex vivo cultures of human prostate tumours. The chemoresistant phenotype of docetaxel-resistant sublines of PC3 and DU145 cell lines was reversed by docetaxel and VS-6063 co-treatment. Mice bearing PC3 tumour xenografts had a greater reduction of tumour growth when treated with docetaxel in combination with VS-6063, compared to those receiving either monotherapy. Human prostate tumour explants cultured with docetaxel combined with VS-6063 displayed a higher percentage of cleaved caspase-3 immunostaining in cancer cells, than those cultured with either agent alone.
Our findings suggest that co-administration of VS-6063 or other FAK inhibitors with docetaxel represents a potential therapeutic strategy to overcome docetaxel resistance in CRPC patients.