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Effect of FAK inhibitor VS-6063 (defactinib) on docetaxel efficacy in prostate cancer

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dc.contributor.authorLin, H.
dc.contributor.authorLee, B.
dc.contributor.authorCastillo, L.
dc.contributor.authorSpielman, C.
dc.contributor.authorGrogan, J.
dc.contributor.authorYeung, N.
dc.contributor.authorKench, J.
dc.contributor.authorStricker, P.
dc.contributor.authorHaynes, A.
dc.contributor.authorCentenera, M.
dc.contributor.authorButler, L.
dc.contributor.authorShreeve, S.
dc.contributor.authorHorvath, L.
dc.contributor.authorDaly, R.
dc.date.issued2018
dc.description.abstractBackground: 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.
dc.description.statementofresponsibilityHui-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
dc.identifier.citationProstate, 2018; 78(4):308-317
dc.identifier.doi10.1002/pros.23476
dc.identifier.issn0270-4137
dc.identifier.issn1097-0045
dc.identifier.orcidCentenera, M. [0000-0002-2206-0632]
dc.identifier.orcidButler, L. [0000-0003-2698-3220]
dc.identifier.urihttp://hdl.handle.net/2440/111573
dc.language.isoen
dc.publisherWiley
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/535903
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1058540
dc.relation.granthttp://purl.org/au-research/grants/arc/FT130101004
dc.rights© 2018 Wiley Periodicals, Inc.
dc.source.urihttps://doi.org/10.1002/pros.23476
dc.subjectChemoresistance; defactinib; Docetaxel; focal adhesion kinase; prostate cancer; VS-6063
dc.titleEffect of FAK inhibitor VS-6063 (defactinib) on docetaxel efficacy in prostate cancer
dc.typeJournal article
pubs.publication-statusPublished

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