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; Roger J. Daly

doi:10.1002/pros.23476

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, Roger J. Daly

Research output: Contribution to journal › Article › Research › peer-review

57 Citations (Scopus)

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	The Prostate
Volume	78
Issue number	4
DOIs	https://doi.org/10.1002/pros.23476
Publication status	Published - 1 Mar 2018

Keywords

chemoresistance
defactinib
Docetaxel
focal adhesion kinase
prostate cancer
VS-6063

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/pros.23476

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@article{179d363d4d72440292e7b988c6b2013e,

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

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.",

keywords = "chemoresistance, defactinib, Docetaxel, focal adhesion kinase, prostate cancer, VS-6063",

author = "Lin, {Hui Ming} and Lee, {Brian Y.} and Lesley Castillo and Calan Spielman and Judith Grogan and Yeung, {Nicole K.} and Kench, {James G.} and Stricker, {Phillip D.} and Haynes, {Anne Maree} and Centenera, {Margaret M.} and Butler, {Lisa M.} and Shreeve, {S. Martin} and Horvath, {Lisa G.} and Daly, {Roger J.}",

year = "2018",

month = mar,

day = "1",

doi = "10.1002/pros.23476",

language = "English",

volume = "78",

pages = "308--317",

journal = "The Prostate",

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publisher = "John Wiley & Sons",

number = "4",

}

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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

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U2 - 10.1002/pros.23476

DO - 10.1002/pros.23476

M3 - Article

AN - SCOPUS:85040829294

SN - 0270-4137

VL - 78

SP - 308

EP - 317

JO - The Prostate

JF - The Prostate

IS - 4

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Molecular markers of phenotype, therapeutic responsiveness and prognosis in human cancers - Improving characterisation of human cancers in order to optimise clinical management and treatment.

Cite this

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Projects

Molecular markers of phenotype, therapeutic responsiveness and prognosis in human cancers - Improving characterisation of human cancers in order to optimise clinical management and treatment.

Cite this