ArticleJournal of hepatology2021
FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids towards cholangiocarcinoma.
Article in Journal of hepatology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers, 1 of them a synthesis that pooled it.
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Who cites it
38 citing papers in PubMed, 1 synthesis or guideline pooled it, 80 citations in OpenAlex.
- Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance.Nature reviews. Gastroenterology & hepatology · 2023Guideline
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- Sequencing of Fibroblast Growth Factor Receptor Inhibitors in Cholangiocarcinoma: A Review of Published Cases.JCO precision oncology · 2026Review
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- How to efficiently establish animal models of cholangiocarcinoma: challenges and inspiration.Medical review (2021) · 2026Review
- Fusion oncoproteins orchestrate tumorigenesis and sustain malignant progression via a positive feedback mechanism.Cell & bioscience · 2026Review
- Fibroblast Growth Factor Receptor (FGFR) Inhibitors for the Treatment of Cholangiocarcinoma: Key Therapeutic Developments and Knowledge Gaps.Drug design, development and therapy · 2026Review
- Research on Targeted Therapy for Malignant Tumors of the Biliary Tract.OncoTargets and therapy · 2026Review
- Pbrm1 Loss Induces a Permissive Chromatin State for Cholangiocytic Differentiation and Cholangiocarcinoma Formation.Cellular and molecular gastroenterology and hepatology · 2026Article
- Next-Generation Hydrogels for Biliary Organoid Engineering.Pharmaceuticals (Basel, Switzerland) · 2025Review
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- ERK1/2 Signaling in Intrahepatic Cholangiocarcinoma: From Preclinical Advances to Therapeutic Strategies.Biology · 2025Review
- Microenvironmental control of the ductular reaction: balancing repair and disease progression.Cell death & disease · 2025Review
- Applications of 3D models in cholangiocarcinoma.Frontiers in oncology · 2025Review
- Deciphering the heterogeneity and plasticity of the tumor microenvironment in liver cancer provides insights for prognosis.Frontiers in pharmacology · 2025Article
- Cancer Organoids as reliable disease models to drive clinical development of novel therapies.Journal of experimental & clinical cancer research : CR · 2024Article
- Targeted therapies in biliary tract cancer-when precision becomes imprecise.ESMO gastrointestinal oncology · 2024Review
- Organoid as a promising tool for primary liver cancer research: a comprehensive review.Cell & bioscience · 2024Review
- Targeting FGFR for cancer therapy.Journal of hematology & oncology · 2024Review
- Integrative genomic analyses of European intrahepatic cholangiocarcinoma: Novel ROS1 fusion gene and PBX1 as prognostic marker.Clinical and translational medicine · 2024Article
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Authors and funding
19 authors at 7 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND &
aimsAbout 15% of intrahepatic cholangiocarcinomas (iCCAs) express fibroblast growth factor receptor 2 (FGFR2) fusion proteins (FFs), usually alongside mutational inactivation of TP53, CDKN2A or BAP1. In FFs, FGFR2 residues 1-768 fuse to sequences encoded by a diverse array of partner genes (>60) causing oncogenic FF activation. While FGFR-specific tyrosine kinase inhibitors (F-TKI) provide clinical benefit in FF
methodsFour iCCA FFs carrying different fusion sequences were expressed in Tp53
resultsTransplantation of FF-expressing liver organoids yielded tumors diagnosed as CCA based on histological, phenotypic and transcriptomic analyses. The penetrance of this tumorigenic phenotype was influenced by FF identity. Tumor organoids and 2D cell lines derived from CCA lesions were addicted to FF signaling via Ras-Erk, regardless of FF identity or V565F mutation. Dual blockade of FF and the Ras-Erk pathway by concomitant pharmacological inhibition of FFs and Mek1/2 provided greater therapeutic efficacy than single agent F-TKI in vitro and in vivo.
conclusionsFF-driven iCCA pathogenesis was successfully modeled on a Tp53 LAY SUMMARY: Intrahepatic cholangiocarcinoma (iCCA) is a rare cancer that is difficult to treat. A subtype of iCCA is caused by genomic alterations that generate oncogenic drivers known as FGFR2 fusions. Patients with FGFR2 fusions respond to FGFR inhibitors, but clinical responses are often of modest duration. We used animal and cellular models to show that FGFR2 fusions require the activity of a downstream effector named Mek1/2. We found that dual blockade of FGFR2 fusions and Mek1/2 was more effective than isolated inhibition of FGFR2 fusions, pointing to the potential clinical utility of dual FGFR2-MEK1/2 blockade in patients with iCCA.
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