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Ref Type Journal Article
PMID (33926920)
Authors Cleary JM, Raghavan S, Wu Q, Li YY, Spurr LF, Gupta HV, Rubinson DA, Fetter IJ, Hornick JL, Nowak JA, Siravegna G, Goyal L, Shi L, Brais LK, Loftus M, Shinagare AB, Abrams TA, Clancy TE, Wang J, Patel AK, Brichory F, Vaslin Chessex A, Sullivan RJ, Keller RB, Denning S, Hill ER, Shapiro GI, Pokorska-Bocci A, Zanna C, Ng K, Schrag D, Janne PA, Hahn WC, Cherniack AD, Corcoran RB, Meyerson M, Daina A, Zoete V, Bardeesy N, Wolpin BM
Title FGFR2 Extracellular Domain In-Frame Deletions are Therapeutically Targetable Genomic Alterations that Function as Oncogenic Drivers in Cholangiocarcinoma.
Journal Cancer discovery
Vol
Issue
Date 2021 Apr 29
URL
Abstract Text We conducted next generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EIDs) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR-1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predict sensitivity to FGFR inhibitors in the clinic.

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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 PHGDH FGFR2 - PHGDH fusion gain of function FGFR2-PHGDH results from the fusion of FGFR2 and PHGDH, which leads constitutive activation of FGFR2 signaling in cell culture and results in tumor formation in a mouse model (PMID: 33926920). FGFR2-PHGDH has been identified in intrahepatic cholangiocarcinoma (PMID: 33926920).
FGFR2 H167_N173del deletion gain of function FGFR2 H167_N173del results in the deletion of seven amino acids in the Ig-like C2-type domain 2 of the Fgfr2 protein from amino acids 167 to 173 (UniProt.org). H167_N173del results in cell transformation (J Clin Oncol 38, 2020 (suppl 4; abstr 567), PMID: 33926920), anchorage-independent growth, constitutive activation of Fgfr2 kinase activity in culture, and tumor formation in an in vivo model (PMID: 33926920).
FGFR2 I288_E295delinsT indel unknown FGFR2 I288_E295delinsT results in deletion of eight amino acids in the Ig-like C2-type domain 3 of the Fgfr2 protein from amino acids 288 to 295, combined with the insertion of a threonine (T) at the same location (UniProt.org). I288_E295delinsT has been identified in the scientific literature (PMID: 33926920), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Dec 2021).
FGFR2 L618F missense unknown FGFR2 L618F (corresponds to L617F in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). L618F in combination with FGFR2 H167_N173del results in constitutive FGFR2 signaling in culture, and has been shown to be associated with secondary resistance to FGFR inhibitors (PMID: 33926920), but has not been individually characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Dec 2021). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF L597Q FGFR2 H167_N173del FGFR2 L618F intrahepatic cholangiocarcinoma no benefit LY3214996 Case Reports/Case Series Actionable In a clinical case study, LY3214996 treatment led to progressive disease after 2 months in an intrahepatic cholangiocarcinoma patient harboring BRAF L597Q, FGFR2 H167_N173del, and FGFR2 L618F (PMID: 33926920). 33926920
FGFR2 H167_N173del intrahepatic cholangiocarcinoma predicted - sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Futibatinib (TAS-120) inhibited growth of an intrahepatic cholangiocarcinoma cell line expressing FGFR2 H167_N173del in culture (PMID: 33926920). 33926920
BRAF L597Q FGFR2 H167_N173del FGFR2 L618F intrahepatic cholangiocarcinoma predicted - resistant Futibatinib Case Reports/Case Series Actionable In a clinical case study, acquisition of BRAF L597Q was identified in an intrahepatic cholangiocarcinoma patient harboring FGFR2 H167_N173del and FGFR2 L618F who developed resistance to treatment with Futibatinib (TAS-120) (PMID: 33926920). 33926920
FGFR2 H167_N173del FGFR2 L618F intrahepatic cholangiocarcinoma predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Futibatinib (TAS-120) treatment led to a partial response with 61% tumor reduction and response duration of 17 months in an intrahepatic cholangiocarcinoma patient harboring FGFR2 H167_N173del and FGFR2 L618F, which was consistent with inhibition of growth in an intrahepatic cholangiocarcinoma cell line expressing FGFR2 H167_N173del and FGFR2 L618F in culture (PMID: 33926920). 33926920
FGFR2 I288_E295delinsT intrahepatic cholangiocarcinoma predicted - sensitive Debio 1347 Case Reports/Case Series Actionable In a clinical case study, Debio1347 treatment in an intrahepatic cholangiocarcinoma patient harboring FGFR2 I288_E395delinsT led to a partial response with a 50% decrease in tumor burden, which was ongoing after 24 months (PMID: 33926920). 33926920
FGFR2 H167_N173del intrahepatic cholangiocarcinoma predicted - sensitive Debio 1347 Case Reports/Case Series Actionable In a Phase I trial, Debio 1347 treatment led to 51% tumor reduction and a progression-free survival of 13 months in an intrahepatic cholangiocarcinoma patient harboring FGFR2 H167_N173del, which was consistent with inhibition of growth in an intrahepatic cholangiocarcinoma cell line expressing FGFR2 H167_N173del in culture (PMID: 33926920; NCT01948297). 33926920
FGFR2 H167_N173del marginal zone B-cell lymphoma predicted - sensitive Debio 1347 Preclinical - Cell culture Actionable In a clinical case study, Debio 1347 treatment in a marginal zone lymphoma patient harboring FGFR2 H167_N173del, who had previously been treated with several lines of therapy, led to a partial response and 36% decrease in tumor burden associated with lymphadenopathy and lung and liver lesions at 16 weeks, with continued response after 7 months (PMID: 33926920). 33926920
BRAF L597Q FGFR2 H167_N173del FGFR2 N550K FGFR2 L618F NRAS Q61K intrahepatic cholangiocarcinoma predicted - resistant LY3214996 Case Reports/Case Series Actionable In a clinical case study, acquired NRAS Q61K and FGFR2 N550K mutations were identified following progression on LY3214996 in an intrahepatic cholangiocarcinoma patient harboring BRAF L597Q, FGFR2 H167_N173del, and FGFR2 L618F (PMID: 33926920). 33926920
FGFR2 H167_N173del FGFR2 L618F intrahepatic cholangiocarcinoma predicted - resistant Debio 1347 Case Reports/Case Series Actionable In a Phase I trial, an intrahepatic cholangioncarcinoma patient who progressed in Debio 1347 was found to have acquired FGFR2 L618F, and co-expression of FGFR2 H167_N173del and FGFR2 L618F an intrahepatic cholangiocarcinoma cell line led to a reduced response to Debio 1347 treatment compared to cells expressing wild-type FGFR2 in culture (PMID: 33926920). 33926920
FGFR2 - PHGDH intrahepatic cholangiocarcinoma predicted - sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Futibatinib (TAS-120) inhibited growth of an intrahepatic cholangiocarcinoma cell line expressing FGFR2-PHGDH in culture PMID: 33926920). 33926920
FGFR2 - PHGDH intrahepatic cholangiocarcinoma predicted - sensitive Debio 1347 Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 inhibited growth of an intrahepatic cholangiocarcinoma cell line expressing FGFR2-PHGDH in culture (PMID: 33926920). 33926920