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Ref Type Journal Article
PMID (32973082)
Authors Sootome H, Fujita H, Ito K, Ochiiwa H, Fujioka Y, Ito K, Miura A, Sagara T, Ito S, Ohsawa H, Otsuki S, Funabashi K, Yashiro M, Matsuo K, Yonekura K, Hirai H
Title Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors.
Journal Cancer research
Vol 80
Issue 22
Date 2020 11 15
URL
Abstract Text FGFR signaling is deregulated in many human cancers, and FGFR is considered a valid target in FGFR-deregulated tumors. Here, we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3, 4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1-4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1-4 with IC50 values of 1.4 to 3.7 nmol/L. Futibatinib covalently bound the FGFR kinase domain, inhibiting FGFR phosphorylation and, in turn, downstream signaling in FGFR-deregulated tumor cell lines. Futibatinib exhibited potent, selective growth inhibition of several tumor cell lines (gastric, lung, multiple myeloma, bladder, endometrial, and breast) harboring various FGFR genomic aberrations. Oral administration of futibatinib led to significant dose-dependent tumor reduction in various FGFR-driven human tumor xenograft models, and tumor reduction was associated with sustained FGFR inhibition, which was proportional to the administered dose. The frequency of appearance of drug-resistant clones was lower with futibatinib than a reversible ATP-competitive FGFR inhibitor, and futibatinib inhibited several drug-resistant FGFR2 mutants, including the FGFR2 V565I/L gatekeeper mutants, with greater potency than any reversible FGFR inhibitors tested (IC50, 1.3-50.6 nmol/L). These results indicate that futibatinib is a novel orally available, potent, selective, and irreversible inhibitor of FGFR1-4 with a broad spectrum of antitumor activity in cell lines and xenograft models. These findings provide a strong rationale for testing futibatinib in patients with tumors oncogenically driven by FGFR genomic aberrations, with phase I to III trials ongoing. SIGNIFICANCE: Preclinical characterization of futibatinib, an irreversible FGFR1-4 inhibitor, demonstrates selective and potent antitumor activity against FGFR-deregulated cancer cell lines and xenograft models, supporting clinical evaluation in patients with FGFR-driven tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/22/4986/F1.large.jpg.

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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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 - TACC3 FGFR3 over exp urinary bladder cancer sensitive Futibatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Futibatinib (TAS-120) treatment led to inhibition of cell proliferation in bladder cancer cell lines with FGFR3 overexpression and harboring FGFR3-TACC3 in culture, and led to inhibition of tumor growth in a cell line xenograft model (PMID: 32973082). 32973082
FGFR2 K310R FGFR2 N549K endometrial cancer predicted - sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Futibatinib (TAS-120) treatment led to inhibition of cell proliferation in an endometrial cancer cell line harboring FGFR2 K310R and FGFR2 N549K in culture (PMID: 32973082). 32973082
FGFR3 rearrange NRAS act mut multiple myeloma no benefit Futibatinib Preclinical - Cell culture Actionable In a preclinical study, a multiple myeloma cell line harboring an FGFR3 rearrangement and an NRAS activating mutation was not sensitive to treatment with Futibatinib (TAS-120) in culture (PMID: 32973082). 32973082
FGFR2 S252W endometrial cancer predicted - sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Futibatinib (TAS-120) treatment led to inhibition of cell proliferation in an endometrial cancer cell line harboring FGFR2 S252W in culture (PMID: 32973082). 32973082
FGFR1 amp lung cancer predicted - sensitive Futibatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Futibatinib (TAS-120) treatment led to inhibition of cell proliferation in lung cancer cell lines harboring FGFR1 amplification in culture, and led to inhibition of tumor growth in a cell line xenograft model with a daily dosing regimen, but not with an intermittent dosing regimen (PMID: 32973082). 32973082
FGFR2 N549K endometrial cancer predicted - sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Futibatinib (TAS-120) treatment led to inhibition of cell proliferation in an endometrial cancer cell line harboring FGFR2 N549K in culture (PMID: 32973082). 32973082
FGFR1 amp FGFR2 amp breast cancer sensitive Futibatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Futibatinib (TAS-120) treatment led to inhibition of cell proliferation in breast cancer cell lines harboring FGFR1 and FGFR2 amplification in culture, and led to inhibition of tumor growth in a cell line xenograft model (PMID: 32973082). 32973082
FGFR3 rearrange FGFR3 K650E multiple myeloma predicted - sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Futibatinib (TAS-120) treatment led to inhibition of cell proliferation in a multiple myeloma cell line harboring an FGFR3 rearrangement and FGFR3 K650E in culture (PMID: 32973082). 32973082
FGFR1 amp breast cancer predicted - sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Futibatinib (TAS-120) treatment led to inhibition of cell proliferation in a breast cancer cell line harboring FGFR1 amplification in culture (PMID: 32973082). 32973082
FGFR3 rearrange FGFR3 F384L multiple myeloma no benefit Futibatinib Preclinical - Cell culture Actionable In a preclinical study, a multiple myeloma cell line harboring an FGFR3 rearrangement and FGFR3 F384L was not sensitive to treatment with Futibatinib (TAS-120) in culture (PMID: 32973082). 32973082
FGFR3 rearrange FGFR3 Y373C multiple myeloma sensitive Futibatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Futibatinib (TAS-120) treatment led to inhibition of cell proliferation in a multiple myeloma cell line harboring an FGFR3 rearrangement and FGFR3 Y373C in culture, and led to tumor regression in a cell line xenograft model (PMID: 32973082). 32973082
FGFR2 K660N FGFR2 amp stomach cancer predicted - resistant AZD4547 Preclinical - Cell culture Actionable In a preclinical study, a gastric cancer cell line harboring an FGFR2 amplification was found to have developed resistance to AZD4547 after prolonged exposure in culture, and was subsequently found to have acquired FGFR2 K660N (PMID: 32973082). 32973082