Reference Detail

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 Cancer discovery
Vol 7
Issue 3
Date 2017 Mar
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
Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 - OPTN fusion unknown FGFR2-OPTN results from the fusion of FGFR2 and OPTN (PMID: 28034880). FGFR2-OPTN has been identified in intrahepatic cholangiocarcinoma (PMID: 28034880), but has not been biochemically characterized and therefore, the effect on fusion protein function is unknown (PubMed, May 2019).
FGFR2 - ZMYM4 fusion unknown FGFR2-ZMYM4 results from the fusion of FGFR2 and ZMYM4 (PMID: 28034880). FGFR2-ZMYM4 has been identified in intrahepatic cholangiocarcinoma (PMID: 28034880, PMID: 31109923), but has not been biochemically characterized and therefore, the effect on fusion protein function is unknown (PubMed, May 2019).
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 vitro (PMID: 28166054), and therefore, is predicted to result in a gain of Fgfr2 protein function. Y
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 vitro (PMID: 28166054), and therefore, is predicted to result in a gain of Fgfr2 protein function. Y
N549D missense unknown FGFR2 N549D lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N549D has been associated with resistance to Fgfr inhibitors in the context of an FGFR2 fusion in culture (PMID: 28034880), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Apr 2019). Y
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 is predicted to confer a gain of function as demonstrated by increased Fgfr2 kinase activity in cell culture (PMID: 25169980), and has been shown to be associated with secondary resistance to FGFR inhibitors (PMID: 28034880). Y
V564M missense unknown FGFR2 V564M lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V564M has been demonstrated to confer resistance to Fgfr inhibitors in cell culture (PMID: 28034880, PMID: 25349422), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Apr 2019). Y
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 is predicted to confer a gain of function as demonstrated by 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). Y
L608V missense unknown FGFR3 L608V lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). L608V has been demonstrated to confer resistance to Fgfr inhibitors in cell culture (PMID: 28034880), but has not been biochemically characterized and therefore, its effect on Fgfr3 protein function is unknown (PubMed, Jan 2019). Y
V555L missense unknown FGFR3 V555L lies within the protein kinase domain of the Fgfr3 protein (UniProt.org). V555L has not been biochemically has been demonstrated to confer resistance to Fgfr inhibitors in cell culture (PMID: 28034880), but has not been biochemically characterized and therefore, its effect on Fgfr3 protein function is unknown (PubMed, Jan 2019). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 V564F Advanced Solid Tumor resistant BGJ398 Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR2 V564F were resistant to BGJ398 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
FGR2 E565A FGFR2 K641R FGFR2 L617V FGFR2 N549H FGFR2 V564F FGFR2-OPTN cholangiocarcinoma predicted - resistant BGJ398 Case Reports/Case Series Actionable In a clinical case study, FGFR2 mutations E565A, K641R, L617V, N549H and V564F were identified in the cell-free DNA of a cholangiocarcinoma patient harboring FGFR2-OPTN fusion after the patient progressed while on Infigratinib (BGJ398) treatment (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 decreased response Debio 1347 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
FGFR2 fusion FGFR2 V564F cholangiocarcinoma predicted - resistant BGJ398 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 Infigratinib (BGJ398) treatment (PMID: 28034880). 28034880
FGFR2 V564F FGFR2-BICC1 cholangiocarcinoma predicted - resistant BGJ398 Case Reports/Case Series Actionable In a clinical case study, FGFR2 V564F was identified in the cell-free DNA of a cholangiocarcinoma patient harboring FGFR2-BICC1 fusion after the patient progressed while on Infigratinib (BGJ398) treatment (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 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 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
FGFR3 L608V Advanced Solid Tumor decreased response Debio 1347 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
FGFR2 E565A FGFR2 K659M FGFR2 N549H FGFR2 N549K FGFR2 V564F FGFR2-ZMYM4 cholangiocarcinoma predicted - resistant BGJ398 Case Reports/Case Series Actionable In a clinical case study, FGFR2 mutations E565A, K659M, N549H, N549K and V564F were identified in the cell-free DNA of a cholangiocarcinoma patient harboring FGFR2-ZMYM4 fusion after the patient progressed while on Infigratinib (BGJ398) treatment (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
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 BGJ398 Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 L608V demonstrated reduced sensitivity to BGJ398 in culture (PMID: 28034880). 28034880
FGFR3 V555M Advanced Solid Tumor resistant BGJ398 Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 V555M were resistant to BGJ398 in culture (PMID: 28034880). 28034880
FGFR3 L608V Advanced Solid Tumor decreased response AZD4547 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 V555M Advanced Solid Tumor resistant AZD4547 Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 V555M were resistant to AZD4547 in culture (PMID: 28034880). 28034880
FGFR3 N540K Advanced Solid Tumor resistant BGJ398 Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 N540K were resistant to BGJ398 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 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 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 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 K650E Advanced Solid Tumor decreased response BGJ398 Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 K650E demonstrated reduced sensitivity to BGJ398 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 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 sensitive Debio 1347 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 Debio 1347 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 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 sensitive 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
FGFR3 V555L Advanced Solid Tumor decreased response BGJ398 Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing FGFR3 V555L demonstrated reduced sensitivity to BGJ398 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