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SORL1-Mediated EGFR and FGFR4 Regulation Enhances Chemoresistance in Ovarian Cancer

Ziyan Jiang1,2, Fangfang Bi2,3, Zhiping Ge1,2

  • 1The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.

Cancers
|January 25, 2025
PubMed

Insights

This study reveals sortilin-related receptor 1 (SORL1) drives carboplatin resistance in ovarian cancer by affecting EGFR and FGFR4 stability. Targeting SORL1 or FGFR4 may improve treatment outcomes for recurrent ovarian cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Recurrent ovarian cancer often exhibits resistance to conventional chemotherapy, posing a significant clinical challenge.
  • Understanding the molecular drivers of chemoresistance is crucial for developing novel targeted therapies.
  • Identifying upregulated genes in recurrent tumors can elucidate mechanisms of treatment failure.

Purpose of the Study:

  • To identify genes upregulated in recurrent ovarian cancer resistant to chemotherapy.
  • To investigate the role of sortilin-related receptor 1 (SORL1) in promoting carboplatin resistance.
  • To explore therapeutic strategies targeting the SORL1/FGFR4 pathway.

Main Methods:

  • Transcriptomic profiling of matched primary and recurrent ovarian tumors.
  • In vitro and in vivo ovarian cancer models to study SORL1 function.
  • Evaluation of an anti-SORL1 antibody and an FGFR4 inhibitor (FGF401) in combination with carboplatin.

Main Results:

  • Sortilin-related receptor 1 (SORL1) was identified as upregulated in recurrent ovarian tumors.
  • SORL1 promotes carboplatin resistance by regulating the stability of epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor 4 (FGFR4).
  • An anti-SORL1 antibody inhibited pro-tumor functions, and FGF401 improved carboplatin efficacy in a mouse model.

Conclusions:

  • The SORL1/FGFR4 pathway plays a critical role in carboplatin resistance in ovarian cancer.
  • Targeting SORL1 or FGFR4 presents a promising therapeutic strategy for recurrent and chemoresistant ovarian cancer.
  • This research offers potential new avenues for improving patient chemoresponse.
Keywords:
EGFRFGFR4SORL1chemoresistance

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