Authors: Chaping Cheng^1,7, Jinming Wang^1,7, Penghui Xu¹, Kai Zhang¹, Zhixiang Xin¹, Huifang Zhao¹, Zhongzhong Ji¹, Man Zhang², Deng Wang^1,2, Yuman He¹, Na Jing^1,2, 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 Gao^1,2 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.