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Combination therapies for targeting FGFR2 fusions in cholangiocarcinoma

Anna Saborowski1, Arndt Vogel1, Oreste Segatto2

  • 1Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Trends in Cancer
|November 29, 2021
PubMed

Insights

Fibroblast growth factor receptor 2 (FGFR2) fusions drive intrahepatic cholangiocarcinoma (iCCA). Targeting RAS-ERK pathways downstream of FGFR2 fusions may improve treatment for unresectable iCCA patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Fibroblast growth factor receptor 2 (FGFR2) fusions are key oncogenic drivers in 10-15% of intrahepatic cholangiocarcinoma (iCCA) cases.
  • Current FGFR-specific inhibitors offer limited, temporary benefits for unresectable FF+ iCCA patients.

Purpose of the Study:

  • To investigate the role of downstream signaling pathways in FGFR2 fusion-driven iCCA.
  • To explore novel therapeutic strategies targeting these pathways for improved iCCA treatment.

Main Methods:

  • Utilized mouse iCCA models to study FGFR2 fusion oncogenesis.
  • Investigated the necessity of the RAS-ERK signaling pathway downstream of FGFR2 fusions.
  • Performed preclinical experiments to evaluate targeted therapies.

Main Results:

  • Documented the essential role of the RAS-ERK pathway in mediating FGFR2 fusion-driven iCCA.
  • Demonstrated the potential of targeting downstream effectors for therapeutic benefit.
  • Provided preclinical evidence for improved FGFR2 fusion targeting strategies.

Conclusions:

  • The RAS-ERK pathway is crucial for FGFR2 fusion-driven iCCA.
  • Targeting downstream pathways like RAS-ERK presents a promising strategy to overcome resistance and improve outcomes in FF+ iCCA.
  • Further preclinical development is warranted to translate these findings into clinical applications.
Keywords:
FGFR tyrosine kinase inhibitorsFGFR2 fusionsintrahepatic cholangiocarcinomamouse models of cholangiocarcinomaresistance to FGFR tyrosine kinase inhibitorstargeted therapies in cholangiocarcinoma

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