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

¹State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 

²School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China. 

³State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China. 

⁴Mabspace Biosciences (Suzhou) Co., Ltd, Suzhou, China. 

⁵Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education & School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China. 

⁶State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. 

⁷These authors contributed equally: Chaping Cheng, Jinming Wang.

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.