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Ref Type Journal Article
PMID (34114373)
Authors Jiang K, Tang X, Guo J, He R, Chan S, Song X, Tu Z, Wang Y, Ren X, Ding K, Zhang Z
Title GZD824 overcomes FGFR1-V561F/M mutant resistance in vitro and in vivo.
Journal Vol Issue Date Pages Journal Short Title
Cancer medicine 10 14 2021 07 4874-4884 Cancer Med
URL
Abstract Text Abnormallyactivated FGFR1 has been validated as a therapeutic target for differentcancers. Although a variety of FGFR inhibitors have shown benefit in manyclinical patients with FGFR1 aberration, FGFR1 mutant resistance such as V561Mmutation, has been reported. To date however, no FGFR inhibitors have beenapproved to treat patients with FGFR mutant resistance. Herein, we report that GZD824, athird generation ABL inhibitor (Phase II, China), overcomes FGFR1-V561F/M mutant resistance in vitro and in vivo. GZD824potently suppresses FGFR1/2/3 with an IC50 value of 4.14 ± 0.96, 2.77 ± 0.082, and 8.10 ± 0.15 nmol/L. It effectively overcomes FGFR1-V561F/M and other mutantresistance in Ba/F3 stable cells (IC50 :8.1-55.0 nM), and effectively inhibits the growth of Ba/F3-FGFR1-V561F/M mutantxenograft tumors in vivo (TGI=73.4%, 49.8% at20mg/kg, p.o, q2d). GZD824may be considered to be an effective drug to treat patients with FGFR1 abnormalactivation or mutant resistance in clinical trials.

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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
FGFR1 K656N missense unknown FGFR1 K656N lies within the protein kinase domain of the Fgfr1 protein (UniProt.org). K656N has been associated with resistance to FGFR inhibitors in culture (PMID: 34114373), and results in increased kinase activity of a truncated Fgfr1 construct in an in vitro assay (PMID: 26864631), but has not been fully biochemically characterized and therefore, its effect on Fgfr1 protein function is unknown. Y
FGFR1 V561F missense unknown FGFR1 V561F lies within the protein kinase domain of the Fgfr1 protein (UniProt.org). V561F has been associated with resistance to FGFR inhibitors in culture (PMID: 34114373), but has not been biochemically characterized and therefore, its effect on Fgfr1 protein function is unknown (PubMed, Oct 2024). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 amp Advanced Solid Tumor predicted - sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, Olverembatinib (HQP1351) inhibited growth of FGFR2 amplified cell lines in culture (PMID: 34114373). 34114373
FGFR1 K656N Advanced Solid Tumor predicted - sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) inhibited growth of a cell line expressing FGFR1 K656N in culture (PMID: 34114373). 34114373
FGFR1 K656E Advanced Solid Tumor predicted - sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Lytgobi (futibatinib) inhibited growth of a cell line expressing FGFR1 K656E in culture (PMID: 34114373). 34114373
FGFR1 V561M Advanced Solid Tumor sensitive Olverembatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Olverembatinib (HQP1351) treatment inhibited cell growth and Fgfr1 phosphorylation and downstream pathway activation in cells expressing FGFR1 V561M in culture and inhibited tumor growth in cell line xenograft models, with a tumor growth inhibition of 49.8% (PMID: 34114373). 34114373
FGFR1 V561F Advanced Solid Tumor predicted - resistant Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing FGFR1 V561F demonstrated insensitivity to Balversa (erdafitinib) in culture (PMID: 34114373). 34114373
FGFR1 K656N Advanced Solid Tumor predicted - sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Lytgobi (futibatinib) inhibited growth of a cell line expressing FGFR1 K656N in culture (PMID: 34114373). 34114373
FGFR1 V561M Advanced Solid Tumor predicted - resistant Futibatinib Preclinical - Cell culture Actionable In a preclinical study, treatment with Lytgobi (futibatinib) failed to inhibit cell growth and Fgfr1 downstream signaling in cells expressing FGFR1 V561M in culture (PMID: 34114373). 34114373
FGFR1 K656N Advanced Solid Tumor predicted - resistant Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing FGFR1 K656N demonstrated insensitivity to Pemazyre (pemigatinib) in culture (PMID: 34114373). 34114373
FGFR1 K656N Advanced Solid Tumor predicted - resistant Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing FGFR1 K656N demonstrated insensitivity to Balversa (erdafitinib) in culture (PMID: 34114373). 34114373
FGFR1 amp Advanced Solid Tumor predicted - sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, Olverembatinib (HQP1351) treatment inhibited cell growth, Fgfr1 phosphorylation, and downstream pathway signaling in cell lines with FGFR1 amplification in culture (PMID: 34114373). 34114373
FGFR1 V561F Advanced Solid Tumor sensitive Olverembatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Olverembatinib (HQP1351) treatment inhibited cell growth, Fgfr1 phosphorylation, and downstream pathway activation and induced cell cycle arrest and apoptosis in cells expressing FGFR1 V561F in culture and inhibited tumor growth in cell line xenograft models, with a tumor growth inhibition of 73.4% (PMID: 34114373). 34114373
FGFR1 K656E Advanced Solid Tumor conflicting Infigratinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing FGFR1 K656E demonstrated insensitivity to Truseltiq (infigratinib) in culture (PMID: 34114373). 34114373
FGFR1 K656E Advanced Solid Tumor conflicting Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing FGFR1 K656E demonstrated insensitivity to Balversa (erdafitinib) in culture (PMID: 34114373). 34114373
FGFR1 K656N Advanced Solid Tumor predicted - sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, Olverembatinib (HQP1351) inhibited growth of a cell line expressing FGFR1 K656N in culture (PMID: 34114373). 34114373
FGFR1 V561F Advanced Solid Tumor predicted - resistant Futibatinib Preclinical - Cell culture Actionable In a preclinical study, treatment with Lytgobi (futibatinib) failed to inhibit cell growth and Fgfr1 downstream signaling in cells expressing FGFR1 V561F in culture (PMID: 34114373). 34114373
FGFR1 K656E Advanced Solid Tumor conflicting Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing FGFR1 K656E demonstrated insensitivity to Pemazyre (pemigatinib) in culture (PMID: 34114373). 34114373
FGFR1 V561F Advanced Solid Tumor predicted - resistant Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, treatment with Pemazyre (pemigatinib) failed to inhibit cell growth and Fgfr1 downstream signaling in cells expressing FGFR1 V561F in culture (PMID: 34114373). 34114373
FGFR1 K656E Advanced Solid Tumor predicted - sensitive Olverembatinib Preclinical - Cell culture Actionable In a preclinical study, Olverembatinib (HQP1351) inhibited growth of a cell line expressing FGFR1 K656E in culture (PMID: 34114373). 34114373
FGFR1 V561F Advanced Solid Tumor resistant Infigratinib Preclinical - Cell line xenograft Actionable In a preclinical study, Truseltiq (infigratinib) treatment failed to inhibit cell growth, Fgfr1 phosphorylation, and downstream pathway activation in cells expressing FGFR1 V561F in culture and failed to inhibit tumor growth in a cell line xenograft model with a tumor growth inhibition of 2.4% (PMID: 34114373). 34114373
FGFR1 V561M Advanced Solid Tumor predicted - resistant Ponatinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing FGFR1 V561M demonstrated insensitivity to Iclusig (ponatinib) in culture (PMID: 34114373). 34114373
FGFR1 V561M Advanced Solid Tumor predicted - resistant Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing FGFR1 V561M demonstrated insensitivity to Balversa (erdafitinib) in culture (PMID: 34114373). 34114373
FGFR1 V561M Advanced Solid Tumor predicted - resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, treatment with Truseltiq (infigratinib) failed to inhibit cell growth and Fgfr1 downstream signaling in cells expressing FGFR1 V561M in culture (PMID: 34114373). 34114373
FGFR1 V561M Advanced Solid Tumor predicted - resistant Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, treatment with Pemazyre (pemigatinib) failed to inhibit cell growth and Fgfr1 downstream signaling in cells expressing FGFR1 V561M in culture (PMID: 34114373). 34114373