In the United States, over 80% of prostate cancer patients die with bone metastases. Second-line hormonal therapies, such as enzalutamide, only improve overall patient survival by a few months in about 50% of patients, and almost all patients develop drug resistance. Thus, there is an urgent need to determine the mechanisms of drug resistance in order to provide better treatments for prostate cancer bone metastasis. Enzalutamide is a small-molecule inhibitor of the androgen receptor. Our study showed that although enzalutamide inhibited the tumor growth of castration-resistant prostate cancer C4-2B cells when xenografted subcutaneously, it had no effect on the growth of C4-2B tumors in the bone or on the development of bone lesions. These data suggested a crucial role of the microenvironment in enzalutamide resistance in prostate cancer bone metastasis. To dissect the role of enzalutamide on the bone microenvironment, we treated bone cells, both osteoblasts and osteoclasts, with enzalutamide. We found that enzalutamide significantly and specifically reduced the TGF-β type II receptor (TGFBR2) protein in osteoblasts. This observation was also confirmed in prostate cancer bone metastatic tissue microarray, in which we performed immunohistochemistry and found a significant decrease of TGFBR2 expression specifically in cancer-associated osteoblasts from patients who had undergone treatment with second-line hormonal therapies, either enzalutamide or abiraterone. Statistical analysis showed that the decrease of TGFBR2 in cancer-associated osteoblasts was a causative effect from the hormonal therapies. To determine the role of TGFBR2 in the osteoblasts during bone metastasis, we used a mouse model (Tgfbr2Col1CreERT KO) with inducible Tgfbr2 knockout specifically in the osteoblasts. We found that loss of TGFBR2 in osteoblasts significantly promoted prostate cancer bone metastasis. Together, our data showed for the first time that reduction of TGFBR2 in osteoblasts by enzalutamide causes resistance to the drug in prostate cancer bone metastasis.

Citation Format: Alexandra Vander Ark, Erica Woodford, Xiangqi Meng, Sourik Ganguly, Xiaotun Zhang, Zachary Madaj, Xiaohong Li. Reduction of TGFBR2 in osteoblasts by enzalutamide causes drug resistance in prostate cancer bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4898.