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.
| Original language | English |
|---|---|
| Pages (from-to) | 308-317 |
| Number of pages | 10 |
| Journal | Prostate |
| Volume | 78 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 1 Mar 2018 |
Keywords
- chemoresistance
- defactinib
- Docetaxel
- focal adhesion kinase
- prostate cancer
- VS-6063
Cite this
}
Effect of FAK inhibitor VS-6063 (defactinib) on docetaxel efficacy in prostate cancer. / Lin, Hui Ming; Lee, Brian Y.; Castillo, Lesley; Spielman, Calan; Grogan, Judith; Yeung, Nicole K.; Kench, James G.; Stricker, Phillip D.; Haynes, Anne Maree; Centenera, Margaret M.; Butler, Lisa M.; Shreeve, S. Martin; Horvath, Lisa G.; Daly, Roger J.
In: Prostate, Vol. 78, No. 4, 01.03.2018, p. 308-317.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Effect of FAK inhibitor VS-6063 (defactinib) on docetaxel efficacy in prostate cancer
AU - Lin, Hui Ming
AU - Lee, Brian Y.
AU - Castillo, Lesley
AU - Spielman, Calan
AU - Grogan, Judith
AU - Yeung, Nicole K.
AU - Kench, James G.
AU - Stricker, Phillip D.
AU - Haynes, Anne Maree
AU - Centenera, Margaret M.
AU - Butler, Lisa M.
AU - Shreeve, S. Martin
AU - Horvath, Lisa G.
AU - Daly, Roger J.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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.
KW - chemoresistance
KW - defactinib
KW - Docetaxel
KW - focal adhesion kinase
KW - prostate cancer
KW - VS-6063
UR - http://www.scopus.com/inward/record.url?scp=85040829294&partnerID=8YFLogxK
U2 - 10.1002/pros.23476
DO - 10.1002/pros.23476
M3 - Article
VL - 78
SP - 308
EP - 317
JO - Prostate
JF - Prostate
SN - 0270-4137
IS - 4
ER -