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Effect of FAK Inhibitor VS-6063 (Defactinib) on Docetaxel Efficacy in Prostate Cancer

Effect of FAK Inhibitor VS-6063 (Defactinib) on Docetaxel Efficacy in Prostate Cancer

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, etc.

Prostate. 2018 Mar;78(4):308-317.

PMID: 29314097

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP114977285	Docetaxel		114977-28-5	Price

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