FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids towards cholangiocarcinoma.
BGJ398
FGFR2 fusions
FGFR2 gatekeeper mutation
FGFR2-BICC1
cholangiocarcinoma
liver organoids
mouse models
targeted therapies
trametinib
Journal
Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
04
06
2020
revised:
03
02
2021
accepted:
25
02
2021
pubmed:
21
3
2021
medline:
8
2
2022
entrez:
20
3
2021
Statut:
ppublish
Résumé
About 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 Four iCCA FFs carrying different fusion sequences were expressed in Tp53 Transplantation 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. FF-driven iCCA pathogenesis was successfully modeled on a Tp53 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.
Sections du résumé
BACKGROUND & AIMS
About 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
METHODS
Four iCCA FFs carrying different fusion sequences were expressed in Tp53
RESULTS
Transplantation 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.
CONCLUSIONS
FF-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.
Identifiants
pubmed: 33741397
pii: S0168-8278(21)00172-0
doi: 10.1016/j.jhep.2021.02.032
pii:
doi:
Substances chimiques
Trp53 protein, mouse
0
Tumor Suppressor Protein p53
0
FGFR2 protein, human
EC 2.7.10.1
Receptor, Fibroblast Growth Factor, Type 2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
351-362Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest All Authors, except M.J.B., have no personal, professional or financial conflicts to disclose. M.J.B. disclosures: ADC Therapeutics – Consulting to self; Exelixis Pharmaceuticals – Consulting to self; Inspyr Therapeutics – Consulting to self; G1 Therapeutics – Consulting to self; Immunovative Therapies – Consulting to self; OncBioMune Pharmaceuticals – Consulting to self; Western Oncolytics – Consulting to self; Lynx Group – Consulting to self; Genentech – Consulting to self; Merck – Consulting to self; Huya – Consulting to self; Astra Zeneca – Travel Support to self. Please refer to the accompanying ICMJE disclosure forms for further details.