創勝集團 - 全整合型國際化生物制藥公司
創勝集團, 生物藥, 抗體, 藥物研發
22 Jun, 2022
Authors: Chaping Cheng1,7, Jinming Wang1,7, Penghui Xu1, Kai Zhang1, Zhixiang Xin1, Huifang Zhao1, Zhongzhong Ji1, Man Zhang2, Deng Wang1,2, Yuman He1, Na Jing1,2, Liancheng Fan1, Kaiyuan Liu1, Fei Li3, Chengcheng Liu1, Yiming Gong1, Suli Cui4, Zhe Sun4, Di Sun4, Xinlai Yao4, Hongjun Li4, Jian Zhang5, Pengcheng Zhang6, Baijun Dong1, Wei Xue1, Xueming Qian4, Wei-Qiang Gao1,2 and Helen He Zhu 1
Abstract: Among the greatest hurdles in clinical management of prostate cancer (PCa) are the progression to lethal castration-resistant prostate cancer (CRPC) and the lack of suitable targeted therapies for advanced disease. Here we identify Gremlin1 as a ligand for fibroblast growth factor receptor 1 (FGFR1), which promotes lineage plasticity and drives castration resistance. Importantly, we generate a specific anti-Gremlin1 therapeutic antibody and demonstrate synergistic effect with androgen deprivation therapy (ADT) in CRPC. GREM1 transcription is suppressed by androgen receptor (AR) and released following ADT. We show that Gremlin1 binds to FGFR1 and activates downstream MAPK signaling. Gremlin1 interacts with FGFR1 differently to its canonical ligand FGF1, as revealed through protein structure docking and mutagenesis experiments. Altogether, our data indicate Gremlin1 as a promising candidate therapeutic target for CRPC.