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Ref Type Journal Article
PMID (28034880)
Authors Goyal L, Saha SK, Liu LY, Siravegna G, Leshchiner I, Ahronian LG, Lennerz JK, Vu P, Deshpande V, Kambadakone A, Mussolin B, Reyes S, Henderson L, Sun JE, Van Seventer EE, Gurski JM, Baltschukat S, Schacher-Engstler B, Barys L, Stamm C, Furet P, Ryan DP, Stone JR, Iafrate AJ, Getz G, Porta DG, Tiedt R, Bardelli A, Juric D, Corcoran RB, Bardeesy N, Zhu AX
Title Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 7 3 2017 Mar 252-263 Cancer Discov
URL
Abstract Text Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the FGFR2 kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intralesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation led to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide the development of future therapeutic strategies.Significance: We report the first genetic mechanisms of clinical acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive ICC. Our findings can inform future strategies for detecting resistance mechanisms and inducing more durable remissions in ICC and in the wide variety of cancers where the FGFR pathway is being explored as a therapeutic target. Cancer Discov; 7(3); 252-63. ©2016 AACR.See related commentary by Smyth et al., p. 248This article is highlighted in the In This Issue feature, p. 235.

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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 K569M missense unknown FGFR2 K569M lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). K569M has been identified in the scientific literature (PMID: 28034880), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, May 2024).
FGFR2 L617V missense gain of function - predicted FGFR2 L617V (also referred to as V618V from the FGFR2IIIb isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). L617V has been shown to confer resistance to Fgfr inhibitors in cell culture (PMID: 28034880), and demonstrates increased Fgfr2 kinase activity compared to wild-type in an in vitro assay (PMID: 28166054), and therefore, is predicted to lead to a gain of Fgfr2 protein function. Y
FGFR2 L618V missense gain of function - predicted FGFR2 L618V (corresponds to L617V in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). L618V has been shown to confer resistance to Fgfr inhibitors in cell culture (PMID: 28034880) and demonstrates increased Fgfr2 kinase activity compared to wild-type in an in vitro assay (PMID: 28166054), and therefore, is predicted to lead to a gain of Fgfr2 protein function. Y
FGFR2 N549D missense gain of function - predicted FGFR2 N549D lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N549D results in proliferation similar to wild-type Fgfr2 in a competition assay but increased transformation activity in cultured cells (PMID: 34272467) and has been associated with resistance to Fgfr inhibitors in the context of an FGFR2 fusion in culture (PMID: 28034880), and therefore, is predicted to lead to a gain of Fgfr2 protein function. Y
FGFR2 V564F missense gain of function - predicted FGFR2 V564F (also referred to as V565F from the FGFR2IIIb isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V564F results in increased kinase activity in cell culture (PMID: 25169980) and has been shown to be associated with secondary resistance to FGFR inhibitors (PMID: 28034880), and therefore, is predicted to lead to a gain of Fgfr2 protein function. Y
FGFR2 V565F missense gain of function - predicted FGFR2 V565F (corresponds to V564F in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V565F results in increased Fgfr2 kinase activity in cell culture (PMID: 25169980) and has been shown to be associated with secondary resistance to FGFR inhibitors (PMID: 28034880, PMID: 31109923), and therefore, is predicted to lead to a gain of Fgfr2 protein function. Y
FGFR3 L608V missense unknown FGFR3 L608V lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). L608V has been identified in the scientific literature (PMID: 28034880, PMID: 37377403), but has not been biochemically characterized and therefore, its effect on Fgfr3 protein function is unknown (PubMed, Feb 2025).
FGFR3 V555L missense unknown FGFR3 V555L lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). V555L has been demonstrated to confer resistance to Fgfr inhibitors in cell culture (PMID: 28034880, PMID: 37377403), but has not been biochemically characterized and therefore, its effect on Fgfr3 protein function is unknown (PubMed, Dec 2024). Y
FGFR3 V555M missense gain of function FGFR3 V555M lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). V555M results in increased Fgfr3 autophosphorylation and substrate phosphorylation in cell culture (PMID: 26992226), and is associated with resistance to Fgfr inhibitors in culture (PMID: 28034880). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 N540K Advanced Solid Tumor decreased response LY2874455 Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 N540K demonstrated reduced sensitivity to LY2874455 in culture (PMID: 28034880). 28034880
FGFR3 K650E Advanced Solid Tumor decreased response Infigratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 K650E demonstrated reduced sensitivity to Truseltiq (infigratinib) in culture (PMID: 28034880). 28034880
FGFR3 N540K Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited proliferation of transformed cells over expressing FGFR3 N540K in culture (PMID: 28034880). 28034880
FGFR3 K650E Advanced Solid Tumor sensitive Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 inhibited proliferation of transformed cells over expressing FGFR3 K650E in culture (PMID: 28034880). 28034880
FGFR3 V555M Advanced Solid Tumor decreased response FIIN-2 Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 V555M demonstrated reduced sensitivity to FIIN-2 in culture (PMID: 28034880). 28034880
FGFR2 V564F Advanced Solid Tumor resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR2 V564F were resistant to Truseltiq (infigratinib) in culture (PMID: 28034880). 28034880
FGFR3 L608V Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited proliferation of transformed cells over expressing FGFR3 L608V in culture (PMID: 28034880). 28034880
FGFR3 L608V Advanced Solid Tumor decreased response Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 L608V demonstrated reduced sensitivity to Debio 1347 in culture (PMID: 28034880). 28034880
FGFR3 L608V Advanced Solid Tumor sensitive LY2874455 Preclinical - Cell culture Actionable In a preclinical study, LY2874455 inhibited proliferation of transformed cells over expressing FGFR3 L608V in culture (PMID: 28034880). 28034880
FGFR3 V555M Advanced Solid Tumor sensitive Dovitinib Preclinical - Cell culture Actionable In a preclinical study, Dovitinib (TKI258) inhibited proliferation of transformed cells over expressing FGFR3 V555M in culture (PMID: 28034880). 28034880
FGFR3 V555M Advanced Solid Tumor sensitive LY2874455 Preclinical - Cell culture Actionable In a preclinical study, LY2874455 inhibited proliferation of transformed cells over expressing FGFR3 V555M in culture (PMID: 28034880). 28034880
FGFR3 V555M Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited proliferation of transformed cells over expressing FGFR3 V555M in culture (PMID: 28034880). 28034880
FGFR3 V555M Advanced Solid Tumor decreased response Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 V555M demonstrated reduced sensitivity to Debio 1347 in culture (PMID: 28034880). 28034880
FGFR3 N540K Advanced Solid Tumor resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 N540K were resistant to Truseltiq (infigratinib) in culture (PMID: 28034880). 28034880
FGFR3 N540K Advanced Solid Tumor decreased response FIIN-2 Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 N540K demonstrated reduced sensitivity to FIIN-2 in culture (PMID: 28034880). 28034880
FGFR3 N540K Advanced Solid Tumor decreased response Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 N540K demonstrated reduced sensitivity to Debio 1347 in culture (PMID: 28034880). 28034880
FGFR3 K650E Advanced Solid Tumor sensitive FIIN-2 Preclinical - Cell culture Actionable In a preclinical study, FIIN-2 inhibited proliferation of transformed cells over expressing FGFR3 K650E in culture (PMID: 28034880). 28034880
FGFR3 N540K Advanced Solid Tumor sensitive Dovitinib Preclinical - Cell culture Actionable In a preclinical study, Dovitinib (TKI258) inhibited proliferation of transformed cells over expressing FGFR3 N540K in culture (PMID: 28034880). 28034880
FGFR3 L608V Advanced Solid Tumor decreased response Infigratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 L608V demonstrated reduced sensitivity to Truseltiq (infigratinib) in culture (PMID: 28034880). 28034880
FGFR3 L608V Advanced Solid Tumor decreased response Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 L608V demonstrated reduced sensitivity to AZD4547 in culture (PMID: 28034880). 28034880
FGFR3 V555L Advanced Solid Tumor decreased response Infigratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 V555L demonstrated reduced sensitivity to Truseltiq (infigratinib) in culture (PMID: 28034880). 28034880
FGFR3 V555M Advanced Solid Tumor resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 V555M were resistant to Truseltiq (infigratinib) in culture (PMID: 28034880). 28034880
FGFR3 K650E Advanced Solid Tumor sensitive LY2874455 Preclinical - Cell culture Actionable In a preclinical study, LY2874455 inhibited proliferation of transformed cells over expressing FGFR3 K650E in culture (PMID: 28034880). 28034880
FGFR3 K650E Advanced Solid Tumor conflicting Dovitinib Preclinical - Cell culture Actionable In a preclinical study, Dovitinib (TKI258) inhibited proliferation of transformed cells over expressing FGFR3 K650E in culture (PMID: 28034880). 28034880
FGFR2 fusion FGFR2 V564F cholangiocarcinoma predicted - resistant Infigratinib Case Reports/Case Series Actionable In a clinical case study, FGFR2 V564F was identified in the cell-free DNA of 3 cholangiocarcinoma patients harboring FGFR2 fusion after the patients progressed while on Truseltiq (infigratinib) treatment (PMID: 28034880). 28034880
FGFR3 V555M Advanced Solid Tumor resistant Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 V555M were resistant to AZD4547 in culture (PMID: 28034880). 28034880
FGFR3 L608V Advanced Solid Tumor sensitive FIIN-2 Preclinical - Cell culture Actionable In a preclinical study, FIIN-2 inhibited proliferation of transformed cells over expressing FGFR3 L608V in culture (PMID: 28034880). 28034880
FGFR3 L608V Advanced Solid Tumor sensitive Dovitinib Preclinical - Cell culture Actionable In a preclinical study, Dovitinib (TKI258) inhibited proliferation of transformed cells over expressing FGFR3 L608V in culture (PMID: 28034880). 28034880
FGFR3 K650E Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited proliferation of transformed cells over expressing FGFR3 K650E in culture (PMID: 28034880). 28034880