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Gremlin1 is a therapeutically targetable FGFR1 ligand that regulates lineage plasticity and castration resistance in prostate cancer

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

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.