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Updated: Mar 4, 2026

Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
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Fibroblast Growth Factor Receptor (FGFR) Inhibitors for the Treatment of Cholangiocarcinoma: Key Therapeutic

Enes Erul1,2, Sergio Cifuentes-Canaval3, Akhil Santhosh4

  • 1Department of Medical Oncology, Ankara University Faculty of Medicine, Ankara University, Ankara, 06590, Türkiye.

Drug Design, Development and Therapy
|March 3, 2026
PubMed

Insights

Fibroblast growth factor receptor 2 (FGFR2) alterations are key drivers in a subset of biliary tract cancers (BTCs), especially intrahepatic cholangiocarcinoma (iCCA). FGFR inhibitors show promise but require careful monitoring for side effects like hyperphosphatemia.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • Fibroblast growth factor receptor 2 (FGFR2) alterations are crucial oncogenic drivers in a specific subset of biliary tract cancers (BTCs), particularly intrahepatic cholangiocarcinoma (iCCA).
  • These alterations, including fusions and mutations, define a distinct molecular subgroup with varying prevalence based on geographic and etiological factors, such as liver fluke association.
  • Other actionable genomic events like IDH1 mutations, BRAF V600E, HER2 amplification, and MSI-H also occur in BTCs.

Purpose of the Study:

  • To review the role of FGFR2 alterations as a targetable oncogenic driver in BTCs.
  • To summarize the clinical activity and toxicity profile of FGFR inhibitors in FGFR2-rearranged iCCA.
  • To discuss the mechanisms of acquired resistance and the development of next-generation inhibitors and combination strategies.

Main Methods:

  • Review of clinical studies on FGFR inhibitors in FGFR2-rearranged iCCA.
  • Analysis of translational work using cell-free DNA (cfDNA)-based liquid biopsy to identify resistance mechanisms.
  • Examination of data on the prevalence and etiological backgrounds of FGFR2 alterations in BTCs.

Main Results:

  • FGFR2 alterations are significant drivers in a distinct subset of BTCs, particularly iCCA.
  • Clinical studies show meaningful activity of FGFR inhibitors in FGFR2-rearranged iCCA, with hyperphosphatemia as a characteristic on-target toxicity.
  • Liquid biopsy identified secondary kinase-domain mutations conferring acquired resistance, guiding the development of new inhibitors and combination therapies.

Conclusions:

  • Comprehensive molecular profiling is essential for optimizing targeted therapy in rare and heterogeneous BTCs.
  • Innovative trial designs, such as umbrella trials, are needed to effectively manage patients with FGFR2-altered BTCs.
  • Next-generation FGFR2 inhibitors and combination strategies (e.g., with EGFR/ERBB blockade) are promising for overcoming resistance and improving outcomes.
Keywords:
FGFR inhibitorsFGFR2 alterationsacquired resistancebiliary tract cancerintrahepatic cholangiocarcinomaliquid biopsy

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