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

Chaping Cheng1, Jinming Wang1, Penghui Xu1

  • 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.

Nature Cancer
|May 27, 2022
PubMed

Insights

Gremlin1 drives castration resistance in prostate cancer by activating FGFR1 signaling. Targeting Gremlin1 with an antibody offers a synergistic therapy with androgen deprivation, representing a promising approach for advanced prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Prostate cancer (PCa) progression to castration-resistant prostate cancer (CRPC) presents a significant clinical challenge.
  • Limited targeted therapies exist for advanced PCa, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To identify novel therapeutic targets for CRPC.
  • To investigate the role of Gremlin1 in promoting castration resistance in prostate cancer.

Main Methods:

  • Identified Gremlin1 as a ligand for fibroblast growth factor receptor 1 (FGFR1).
  • Generated a specific anti-Gremlin1 therapeutic antibody.
  • Utilized protein structure docking and mutagenesis to analyze Gremlin1-FGFR1 interaction.
  • Assessed synergistic effects with androgen deprivation therapy (ADT).

Main Results:

  • Gremlin1 promotes lineage plasticity and drives castration resistance in PCa.
  • GREM1 transcription is suppressed by the androgen receptor (AR) and upregulated after ADT.
  • Gremlin1 activates downstream MAPK signaling via FGFR1.
  • Anti-Gremlin1 antibody demonstrated synergistic effects with ADT in CRPC models.

Conclusions:

  • Gremlin1 is a key driver of castration resistance in prostate cancer.
  • Targeting Gremlin1 with therapeutic antibodies represents a promising strategy for CRPC treatment.
  • Gremlin1-FGFR1 axis offers a novel therapeutic avenue for advanced prostate cancer.

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