State 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.
School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Nat Cancer. 2022 May;3(5):565-580. doi: 10.1038/s43018-022-00380-3. Epub 2022 May 27.
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.
在前列腺癌（PCa）的临床管理中，最大的障碍之一是进展为致命的去势抵抗性前列腺癌（CRPC），以及缺乏针对晚期疾病的合适靶向治疗方法。在这里，我们确定 Gremlin1 是成纤维细胞生长因子受体 1（FGFR1）的配体，它促进谱系可塑性并驱动去势抵抗。重要的是，我们生成了一种特异性的抗 Gremlin1 治疗性抗体，并在 CRPC 中证明与雄激素剥夺疗法（ADT）具有协同作用。GREM1 转录受雄激素受体（AR）抑制，并在 ADT 后释放。我们表明 Gremlin1 与 FGFR1 结合并激活下游 MAPK 信号。通过蛋白质结构对接和突变实验表明，Gremlin1 与 FGFR1 的结合方式与其典型配体 FGF1 不同。总的来说，我们的数据表明 Gremlin1 是 CRPC 的一个有前途的治疗靶点候选物。
