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Ref Type Journal Article
PMID (33741397)
Authors Cristinziano G, Porru M, Lamberti D, Buglioni S, Rollo F, Amoreo CA, Manni I, Giannarelli D, Cristofoletti C, Russo G, Borad MJ, Grazi GL, Diodoro MG, Giordano S, Sacconi A, Forcato M, Anastasi S, Leonetti C, Segatto O
Title FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids towards cholangiocarcinoma.
Journal Journal of hepatology
Vol 75
Issue 2
Date 2021 Aug
URL
Abstract Text 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+ iCCA, responses are partial and/or limited by resistance mechanisms, such as the V565F substitution in the FGFR2 gatekeeper residue. Improving on FF targeting in iCCA therefore remains a critical unmet need. Herein, we aimed to generate a murine model of FF-driven iCCA and use this to uncover actionable FF-associated dependencies.Four iCCA FFs carrying different fusion sequences were expressed in Tp53-/- mouse liver organoids. Tumorigenic properties of genetically modified liver organoids were assessed by transplantation into immuno-deficient mice. Cellular models derived from neoplastic lesions were exploited for pre-clinical studies.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-/- murine background, revealing biological heterogeneity among structurally different FFs. Double blockade of FF-ERK signaling deserves consideration for precision-based approaches against human FF+ iCCA.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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 OGA FGFR2 - OGA fusion gain of function - predicted FGFR2-OGA results from the fusion of FGFR2 and OGA (PMID: 24550739), is associated with increased Fgfr2 expression and phosphorylation of Frs2 and Erk in patient tissue (PMID: 24550739), results in constitutive Fgfr2 phosphorylation in culture, but not does induce tumor growth in a mouse model (PMID: 33741397), and therefore, is predicted to lead to a gain of protein function. FGFR2-OGA has been identified in intrahepatic cholangiocarcinoma (PMID: 33741397).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 - BICC1 intrahepatic cholangiocarcinoma sensitive Infigratinib Preclinical Actionable In a preclinical study, Truseltiq (infigratinib) treatment reduced growth and viability of cells derived from a TP53-null intrahepatic cholangiocarcinoma mouse model expressing FGFR2-BICC1 fusion in tumoroid and 2D cell culture, and resulted in a 60% partial response rate in a subcutaneous allograft mouse model (PMID: 33741397). 33741397
FGFR2 - BICC1 intrahepatic cholangiocarcinoma no benefit Trametinib Preclinical Actionable In a preclinical study, Mekinist (trametinib) treatment inhibited growth and viability of cells derived from a TP53-null intrahepatic cholangiocarcinoma mouse model expressing FGFR2-BICC1 fusion in tumoroid and 2D cell culture, but demonstrated only marginal growth inhibition in a subcutaneous allograft mouse model (PMID: 33741397). 33741397
FGFR2 - BICC1 intrahepatic cholangiocarcinoma sensitive Infigratinib + Trametinib Preclinical Actionable In a preclinical study, Truseltiq (infigratinib) and Mekinist (trametinib) combination treatment synergistically reduced viability of cells derived from a TP53-null intrahepatic cholangiocarcinoma mouse model expressing FGFR2-BICC1 fusion and induced a partial response in 100% of tumors in a subcutaneous allograft mouse model (PMID: 33741397). 33741397
FGFR2 - CCDC6 intrahepatic cholangiocarcinoma sensitive Infigratinib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) and Mekinist (trametinib) combination treatment synergistically reduced viability of tumoroids derived from a TP53-null intrahepatic cholangiocarcinoma mouse model expressing FGFR2-CCDC6 fusion (PMID: 33741397). 33741397
FGFR2 - CCDC6 intrahepatic cholangiocarcinoma sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) treatment reduced growth of tumoroids derived from a TP53-null intrahepatic cholangiocarcinoma mouse model expressing FGFR2-CCCD6 fusion in culture (PMID: 33741397). 33741397
FGFR2 - TACC3 FGFR2 V565F intrahepatic cholangiocarcinoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) treatment reduced viability of cells derived from a TP53-null intrahepatic cholangiocarcinoma mouse model expressing FGFR2 V565F in the context of FGFR2-TACC3 fusion in culture (PMID: 33741397). 33741397
FGFR2 - TACC3 intrahepatic cholangiocarcinoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) treatment inhibited growth and viability of cells derived from a TP53-null intrahepatic cholangiocarcinoma mouse model expressing FGFR2-TACC3 fusion in tumoroid and 2D cell culture (PMID: 33741397). 33741397
FGFR2 - TACC3 FGFR2 V565F intrahepatic cholangiocarcinoma resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, treatment with Truseltiq (infigratinib) did not inhibit growth of cells derived from a TP53-null mouse liver tumoroid expressing FGFR2 V565F in the context of FGFR2-TACC3 fusion in culture (PMID: 33741397). 33741397
FGFR2 - TACC3 intrahepatic cholangiocarcinoma sensitive Infigratinib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) and Mekinist (trametinib) combination treatment synergistically reduced viability of cells derived from a TP53-null intrahepatic cholangiocarcinoma mouse model expressing FGFR2-TACC3 fusion (PMID: 33741397). 33741397
FGFR2 - CCDC6 intrahepatic cholangiocarcinoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) treatment reduced growth of tumoroids derived from a TP53-null intrahepatic cholangiocarcinoma mouse model expressing FGFR2-CCDC6 fusion in culture (PMID: 33741397). 33741397
FGFR2 - TACC3 intrahepatic cholangiocarcinoma sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) treatment inhibited Fgfr2 signaling and reduced growth and viability of cells derived from a TP53-null intrahepatic cholangiocarcinoma mouse model expressing FGFR2-TACC3 fusion in tumoroid and 2D cell culture (PMID: 33741397). 33741397