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Ref Type Journal Article
PMID (31109923)
Authors Goyal L, Shi L, Liu LY, Fece de la Cruz F, Lennerz JK, Raghavan S, Leschiner I, Elagina L, Siravegna G, Ng RWS, Vu P, Patra KC, Saha SK, Uppot RN, Arellano R, Reyes S, Sagara T, Otsuki S, Nadres B, Shahzade HA, Dey-Guha I, Fetter IJ, Baiev I, Van Seventer EE, Murphy JE, Ferrone CR, Tanabe KK, Deshpande V, Harding JJ, Yaeger R, Kelley RK, Bardelli A, Iafrate AJ, Hahn WC, Benes CH, Ting DT, Hirai H, Getz G, Juric D, Zhu AX, Corcoran RB, Bardeesy N
Title TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 9 8 2019 Aug 1064-1079 Cancer Discov
URL
Abstract Text ATP-competitive fibroblast growth factor receptor (FGFR) kinase inhibitors, including BGJ398 and Debio 1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring activating FGFR2 gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary FGFR2 kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor TAS-120 demonstrated efficacy in 4 patients with FGFR2 fusion-positive ICC who developed resistance to BGJ398 or Debio 1347. Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio 1347. Functional assessment and modeling the clonal outgrowth of individual resistance mutations from polyclonal cell pools mirrored the resistance profiles observed clinically for each inhibitor. Our findings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsy and ctDNA analysis, may prolong the duration of benefit from FGFR inhibition in patients with FGFR2 fusion-positive ICC. SIGNIFICANCE: ATP-competitive FGFR inhibitors (BGJ398, Debio 1347) show efficacy in FGFR2-altered ICC; however, acquired FGFR2 kinase domain mutations cause drug resistance and tumor progression. We demonstrate that the irreversible FGFR inhibitor TAS-120 provides clinical benefit in patients with resistance to BGJ398 or Debio 1347 and overcomes several FGFR2 mutations in ICC models.This article is highlighted in the In This Issue feature, p. 983.

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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
Futibatinib Futibatinib 136 9
Infigratinib Infigratinib 178 15
Drug Name Trade Name Synonyms Drug Classes Drug Description
Futibatinib Lytgobi TAS-120 FGFR Inhibitor (Pan) 26 Lytgobi (futibatinib) is a third-generation pan-FGFR inhibitor, which results in the inhibition of FGFR-mediated signal transduction pathways and tumor cell proliferation (PMID: 31109923). Lytgobi (futibatinib) is FDA approved for use in patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 fusion or rearrangement (FDA.gov).
Infigratinib Truseltiq BGJ398|BGJ-398|BGJ 398 FGFR Inhibitor (Pan) 26 Truseltiq (infigratinib) is a pan-FGFR inhibitor, which inhibits tumor angiogenesis and tumor cell proliferation (PMID: 31109923, PMID: 30101387). Truseltiq (infigratinib) is FDA approved for use in patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma harboring FGFR2 fusion or rearrangement (FDA.gov).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 E566A missense gain of function FGFR2 E566A (corresponds to E565A in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). E566A results in increased Fgfr2 autophosphorylation and substrate phosphorylation in in vitro kinase assays (PMID: 17803937, PMID: 28166054) and is also associated with resistance to FGFR inhibitors (PMID: 31109923). Y
FGFR2 H683L missense unknown FGFR2 H683L (corresponds to H682L in the canonical isoform) lies within the protein kinase domain of the FGFR2 protein (UniProt.org). H683L has been associated with resistance to Fgfr inhibitors in the context of an FGFR2 fusion in culture (PMID: 31109923), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Jul 2024). Y
FGFR2 K660M missense unknown FGFR2 K660M (corresponds to K659M in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). K660M has been associated with resistance to Fgfr inhibitors in the context of an FGFR2 fusion (PMID: 31109923), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2024). Y
FGFR2 K714R missense unknown FGFR2 K714R (also referred to as K715R from the FGFR2IIIb isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). K714R may be associated with resistance to Fgfr inhibitors, as the corresponding K715R variant in isoform IIIb has been associated with resistance to Fgfr inhibition in the context of an FGFR2 fusion (PMID: 31109923), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2024).
FGFR2 K715R missense unknown FGFR2 K715R (corresponds to K714R in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). K715R has been associated with resistance to Fgfr inhibitors in the context of an FGFR2 fusion (PMID: 31109923), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2024). Y
FGFR2 V563L missense gain of function - predicted FGFR2 V563L (corresponds to V562L in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V563L is predicted to confer a gain of function to the Fgfr2 protein as indicated by increased Fgfr2 kinase activity in cell culture, and has been shown to be associated with secondary resistance to FGFR inhibitors (PMID: 25169980, PMID: 31109923). 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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 fusion FGFR2 E566A intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Lytgobi (futibatinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 E566A were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 M538I intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Lytgobi (futibatinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 M538I were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 N550H intrahepatic cholangiocarcinoma decreased response Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 N550H had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 H683L intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Lytgobi (futibatinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 H683L were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 H683L intrahepatic cholangiocarcinoma decreased response Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 H683L had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 N550K intrahepatic cholangiocarcinoma resistant Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 N550K were resistant to treatment, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 K660M intrahepatic cholangiocarcinoma resistant Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 K660M were resistant to treatment, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 N550H intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Lytgobi (futibatinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 N550H were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 N550K intrahepatic cholangiocarcinoma resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 N550K were resistant to treatment as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 K660M intrahepatic cholangiocarcinoma resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 K660M were resistant to treatment as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 V565F intrahepatic cholangiocarcinoma decreased response Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 V565F had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 N550K intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Lytgobi (futibatinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 N550K were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 E566A intrahepatic cholangiocarcinoma decreased response Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 E566A had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 V565F intrahepatic cholangiocarcinoma resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 V565F were resistant to treatment as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 K715R intrahepatic cholangiocarcinoma sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 K715R were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling, in in vitro assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 M538I intrahepatic cholangiocarcinoma decreased response Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 M538I had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 K660M intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Lytgobi (futibatinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 K660M were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 K715R intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Lytgobi (futibatinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 K715R were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 L618V intrahepatic cholangiocarcinoma resistant Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 L618V were resistant to treatment, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 V565F intrahepatic cholangiocarcinoma resistant Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Lytgobi (futibatinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 V565F were resistant to treatment, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 H683L intrahepatic cholangiocarcinoma decreased response Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 H683L had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 N550H intrahepatic cholangiocarcinoma decreased response Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 N550H had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 E566A intrahepatic cholangiocarcinoma decreased response Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 E566A had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 K715R intrahepatic cholangiocarcinoma sensitive Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 K715R were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling, in in vitro assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 L618V intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Lytgobi (futibatinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 L618V were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 L618V intrahepatic cholangiocarcinoma resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 L618V were resistant to treatment as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 M538I intrahepatic cholangiocarcinoma decreased response Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 M538I had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923