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Ref Type Journal Article
PMID (25608663)
Authors Sia D, Losic B, Moeini A, Cabellos L, Hao K, Revill K, Bonal D, Miltiadous O, Zhang Z, Hoshida Y, Cornella H, Castillo-Martin M, Pinyol R, Kasai Y, Roayaie S, Thung SN, Fuster J, Schwartz ME, Waxman S, Cordon-Cardo C, Schadt E, Mazzaferro V, Llovet JM
Title Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma.
Journal Nature communications
Vol 6
Issue
Date 2015 Jan 22
URL
Abstract Text Intrahepatic cholangiocarcinoma (iCCA) is a fatal bile duct cancer with dismal prognosis and limited therapeutic options. By performing RNA- and exome-sequencing analyses, we report a novel fusion event, FGFR2-PPHLN1 (16%), and damaging mutations in the ARAF oncogene (11%). Here we demonstrate that the chromosomal translocation t(10;12)(q26;q12) leading to FGFR2-PPHLN1 fusion possesses transforming and oncogenic activity, which is successfully inhibited by a selective FGFR2 inhibitor in vitro. Among the ARAF mutations, N217I and G322S lead to activation of the pathway and N217I shows oncogenic potential in vitro. Screening of a cohort of 107 iCCA patients reveals that FGFR2 fusions represent the most recurrent targetable alteration (45%, 17/107), while they are rarely present in other primary liver tumours (0/100 of hepatocellular carcinoma (HCC); 1/21 of mixed iCCA-HCC). Taken together, around 70% of iCCA patients harbour at least one actionable molecular alteration (FGFR2 fusions, IDH1/2, ARAF, KRAS, BRAF and FGF19) that is amenable for therapeutic targeting.

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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 BICC1 FGFR2 - BICC1 fusion gain of function FGFR2-BICC1 results from the fusion of FGFR2 and BICC1, resulting in the ability to induce oligomerization, Fgfr kinase activity, Mapk signaling and transformation of cells in culture and in animal models (PMID: 23558953, PMID: 24122810, PMID: 28416604). FGFR2-BICC1 has been identified in intrahepatic cholangiocarcinoma (PMID: 25608663, PMID: 31899106).
FGFR2 PPHLN1 FGFR2 - PPHLN1 fusion gain of function FGFR2-PPHLN1 results from the fusion of FGFR2 and PPHLN1 (PMID: 25608663), resulting in constitutive phosphorylation of the fusion protein and activation of downstream Erk1/2 signaling, and is transforming in culture (PMID: 25608663). FGFR2-PPHLN1 has been identified in intrahepatic cholangiocarcinoma (PMID: 25608663).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 - PPHLN1 Advanced Solid Tumor sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) inhibited growth of transformed cells expressing FGFR2-PPHLN1 in culture (PMID: 25608663). 25608663
FGFR2 - PPHLN1 cholangiocarcinoma sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) inhibited viability and migration of cholangiocarcinoma cells expressing FGFR2-PPHLN1 in culture (PMID: 25608663). 25608663