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
Cancer Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
St Vincent's Clinical School, The University of New South Wales, Darlinghurst, New South Wales, Australia.
Prostate. 2018 Mar;78(4):308-317. doi: 10.1002/pros.23476. Epub 2018 Jan 5.
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.
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.
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.
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.
多西他赛是转移性去势抵抗性前列腺癌（CRPC）的标准化疗药物，当与雄激素剥夺疗法联合使用时，也可提高转移性去势敏感性前列腺癌（CSPC）患者的生存率。粘着斑激酶（FAK）激活是前列腺癌细胞中多西他赛耐药的介导因素。本研究的目的是在临床前CRPC和CSPC模型中研究第二代FAK抑制剂VS-6063对多西他赛疗效的影响。
用VS-6063和/或多西他赛或溶剂对照处理多西他赛耐药的CRPC细胞、携带PC3异种移植瘤的小鼠以及患者来源的原发性前列腺肿瘤的体外培养物。使用细胞计数、免疫印迹和免疫组织化学技术评估治疗效果。
与单一疗法相比，多西他赛和VS-6063联合治疗导致多西他赛耐药的CRPC细胞活力下降更大，对PC3异种移植瘤生长的抑制作用更强。人原发性前列腺癌中FAK表达与肿瘤晚期呈正相关。与单一疗法相比，用多西他赛和VS-6063共同培养的患者来源的前列腺肿瘤外植体显示癌细胞凋亡百分比更高。
我们的研究结果表明，FAK抑制剂VS-6063与多西他赛联合给药是克服前列腺癌多西他赛耐药的一种潜在治疗策略。
