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Ref Type Journal Article
PMID (38231480)
Authors Wang P, Zhang Y, Xiang R, Yang J, Xu Y, Deng T, Zhou W, Wang C, Xiao X, Wang S
Title Foretinib is effective in acute myeloid leukemia by inhibiting FLT3 and overcoming secondary mutations that drive resistance to quizartinib and gilteritinib.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 2024 Jan 17 Cancer Res
URL
Abstract Text FLT3 internal tandem duplication (FLT3-ITD) mutations are one of the most prevalent somatic alterations associated with poor prognosis in patients with acute myeloid leukemia (AML). The clinically-approved FLT3 kinase inhibitors gilteritinib and quizartinib improve the survival of AML patients with FLT3-ITD mutations, but their long-term efficacy is limited by acquisition of secondary drug-resistant mutations. In this study, we conducted virtual screening of a library of 60411 small molecules and identified foretinib as a potent FLT3 inhibitor. An integrated analysis of the BeatAML database showed that foretinib had a lower IC50 value than other existing FLT3 inhibitors in FLT3-ITD AML patients. Foretinib directly bound to FLT3 and effectively inhibited FLT3 signaling. Foretinib potently inhibited proliferation and promoted apoptosis in human AML cell lines and primary AML cells with FLT3-ITD mutations. Foretinib also significantly extended the survival of mice bearing cell-derived and patient-derived FLT3-ITD xenografts, exhibiting stronger efficacy than clinically-approved FLT3 inhibitors in treating FLT3-ITD AML. Moreover, foretinib showed potent activity against secondary mutations of FLT3-ITD that confer resistance to quizartinib and gilteritinib. These findings support the potential of foretinib for treating AML patients with FLT3-ITD mutations, especially for those carrying secondary mutations after treatment failure with other FLT3 inhibitors.

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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
FLT3 N676K hematologic cancer resistant Quizartinib Preclinical - Cell culture Actionable In a preclinical study, cultured cells expressing FLT3 N676K were resistant to treatment with Vanflyta (quizartinib) (PMID: 38231480). 38231480
FLT3 D835V hematologic cancer resistant Quizartinib Preclinical - Cell culture Actionable In a preclinical study, cultured cells expressing FLT3 D835V were resistant to treatment with Vanflyta (quizartinib) (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 Y842C hematologic cancer sensitive Foretinib Preclinical - Cell line xenograft Actionable In a preclinical study, Foretinib (GSK1363089) inhibited viability of cultured cells expressing FLT3-ITD with FLT3 Y842C and improved survival in a cell line xenograft model (PMID: 38231480). 38231480
FLT3 D835Y hematologic cancer sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited viability of cultured cells expressing FLT3 D835Y (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 F691L hematologic cancer resistant Quizartinib Preclinical - Cell line xenograft Actionable In a preclinical study, cells expressing FLT3-ITD and FLT3 F691L were resistant to treatment with Vanflyta (quizartinib) in culture and in a cell line xenograft model (PMID: 38231480). 38231480
FLT3 Y842C hematologic cancer sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited viability of cultured cells expressing FLT3 Y842C (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 D835V acute myeloid leukemia sensitive Foretinib Preclinical - Cell culture Actionable In a preclinical study, Foretinib (GSK1363089) inhibited viability of primary patient-derived acute myeloid leukemia blasts harboring FLT3-ITD with FLT3 D835V in culture (PMID: 38231480). 38231480
FLT3 exon 14 ins acute myeloid leukemia sensitive Foretinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Foretinib (GSK1363089) inhibited viability of cell lines and primary patient-derived acute myeloid leukemia cells harboring FLT3-ITD in culture, led to decreased tumor burden and improved survival in a cell line and a patient-derived xenograft (PDX) model (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 D835V hematologic cancer sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited viability of cultured cells expressing FLT3-ITD with FLT3 D835V (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 Y842C hematologic cancer sensitive Gilteritinib Preclinical - Cell line xenograft Actionable In a preclinical study, Xospata (gilteritinib) inhibited viability of cultured cells expressing FLT3-ITD with FLT3 Y842C and improved survival in a cell line xenograft model (PMID: 38231480). 38231480
FLT3 D835V hematologic cancer sensitive Foretinib Preclinical - Cell culture Actionable In a preclinical study, Foretinib (GSK1363089) inhibited viability of cultured cells expressing FLT3 D835V (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 D835Y acute myeloid leukemia sensitive Foretinib Preclinical - Cell culture Actionable In a preclinical study, Foretinib (GSK1363089) inhibited viability of primary patient-derived acute myeloid leukemia blasts harboring FLT3-ITD with FLT3 D835Y in culture (PMID: 38231480). 38231480
FLT3 D835V acute myeloid leukemia decreased response Quizartinib Preclinical - Cell culture Actionable In a preclinical study, primary patient-derived acute myeloid leukemia blasts harboring FLT3 D835V were less sensitive to Vanflyta (quizartinib) in culture (PMID: 38231480). 38231480
FLT3 D835V acute myeloid leukemia sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited viability of primary patient-derived acute myeloid leukemia blasts harboring FLT3 D835V in culture (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 D835Y acute myeloid leukemia sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited viability of primary patient-derived acute myeloid leukemia blasts harboring FLT3-ITD with FLT3 D835Y in culture (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 D835V hematologic cancer sensitive Foretinib Preclinical - Cell culture Actionable In a preclinical study, Foretinib (GSK1363089) inhibited viability of cultured cells expressing FLT3-ITD with FLT3 D835V (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 D835Y hematologic cancer sensitive Gilteritinib Preclinical - Cell line xenograft Actionable In a preclinical study, Xospata (gilteritinib) inhibited viability of cultured cells expressing FLT3-ITD with FLT3 D835Y and improved survival in a cell line xenograft model (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 D835Y hematologic cancer sensitive Foretinib Preclinical - Cell line xenograft Actionable In a preclinical study, Foretinib (GSK1363089) inhibited viability of cultured cells expressing FLT3-ITD with FLT3 D835Y, and led to improved survival in a cell line xenograft model (PMID: 38231480). 38231480
FLT3 exon 14 ins NRAS G12C acute myeloid leukemia resistant Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, acute myeloid leukemia cells harboring FLT3-ITD and expressing NRAS G12C were resistant to Xospata (gilteritinib) in culture (PMID: 38231480). 38231480
FLT3 D835E acute myeloid leukemia decreased response Quizartinib Preclinical - Cell culture Actionable In a preclinical study, primary patient-derived acute myeloid leukemia blasts harboring FLT3 D835E were less sensitive to Vanflyta (quizartinib) in culture (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 D835Y acute myeloid leukemia resistant Quizartinib Preclinical - Cell culture Actionable In a preclinical study, primary patient-derived acute myeloid leukemia blasts harboring FLT3-ITD with FLT3 D835Y were less sensitive to Vanflyta (quizartinib) in culture (PMID: 38231480). 38231480
FLT3 Y842C hematologic cancer sensitive Foretinib Preclinical - Cell culture Actionable In a preclinical study, Foretinib (GSK1363089) inhibited viability of cultured cells expressing FLT3 Y842C (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 D835V hematologic cancer resistant Quizartinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing FLT3-ITD with FLT3 D835V were resistant to treatment with Vanflyta (quizartinib) in culture (PMID: 38231480). 38231480
FLT3 D835E acute myeloid leukemia sensitive Foretinib Preclinical - Cell culture Actionable In a preclinical study, Foretinib (GSK1363089) inhibited viability of primary patient-derived acute myeloid leukemia blasts harboring FLT3 D835E in culture (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 D835V acute myeloid leukemia sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited viability of primary patient-derived acute myeloid leukemia blasts harboring FLT3-ITD with FLT3 D835V in culture (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 F691L hematologic cancer sensitive Foretinib Preclinical - Cell line xenograft Actionable In a preclinical study, Foretinib (GSK1363089) inhibited viability of cultured cells expressing FLT3-ITD with FLT3 F691L, and inhibited tumor cell growth in a cell line xenograft model (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 D835Y hematologic cancer resistant Quizartinib Preclinical - Cell line xenograft Actionable In a preclinical study, cells expressing FLT3-ITD with FLT3 D835Y were resistant to treatment with Vanflyta (quizartinib) in culture and in a cell line xenograft model (PMID: 38231480). 38231480
FLT3 D835E acute myeloid leukemia sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited viability of primary patient-derived acute myeloid leukemia blasts harboring FLT3 D835E in culture (PMID: 38231480). 38231480
FLT3 exon 14 ins NRAS G12C acute myeloid leukemia decreased response Foretinib Preclinical - Cell culture Actionable In a preclinical study, acute myeloid leukemia cells harboring FLT3-ITD and expressing NRAS G12C were less sensitive to Foretinib (GSK1363089) in culture (PMID: 38231480). 38231480
FLT3 D835V acute myeloid leukemia sensitive Foretinib Preclinical - Cell culture Actionable In a preclinical study, Foretinib (GSK1363089) inhibited viability of primary patient-derived acute myeloid leukemia blasts harboring FLT3 D835V in culture (PMID: 38231480). 38231480
FLT3 N676K hematologic cancer sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited viability of cultured cells expressing FLT3 N676K (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 Y842C hematologic cancer resistant Quizartinib Preclinical - Cell line xenograft Actionable In a preclinical study, cells expressing FLT3-ITD and FLT3 Y842C were resistant to treatment with Vanflyta (quizartinib) in culture and in a cell line xenograft model (PMID: 38231480). 38231480
FLT3 exon 14 ins hematologic cancer sensitive Foretinib Preclinical - Cell line xenograft Actionable In a preclinical study, Foretinib (GSK1363089) inhibited growth of cultured cells expressing FLT3-ITD mutations, and led to decreased tumor burden and improved survival in a cell line xenograft model (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 F691L hematologic cancer resistant Gilteritinib Preclinical - Cell line xenograft Actionable In a preclinical study, Xospata (gilteritinib) was not active against cells expressing FLT3-ITD with FLT3 F691L in culture and resulted in minimal survival benefit in a cell line xenograft model (PMID: 38231480). 38231480
FLT3 D835V hematologic cancer sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited viability of cultured cells expressing FLT3 D835V (PMID: 38231480). 38231480
FLT3 D835Y hematologic cancer conflicting Quizartinib Preclinical - Cell culture Actionable In a preclinical study, cultured cells expressing FLT3 D835Y were resistant to treatment with Vanflyta (quizartinib) (PMID: 38231480). 38231480
FLT3 D835Y hematologic cancer sensitive Foretinib Preclinical - Cell culture Actionable In a preclinical study, Foretinib (GSK1363089) inhibited viability of cultured cells expressing FLT3 D835Y (PMID: 38231480). 38231480
FLT3 exon 14 ins NRAS G12C acute myeloid leukemia resistant Quizartinib Preclinical - Cell culture Actionable In a preclinical study, acute myeloid leukemia cells harboring FLT3-ITD and expressing NRAS G12C were resistant to Vanflyta (quizartinib) in culture (PMID: 38231480). 38231480
FLT3 exon 14 ins FLT3 D835V acute myeloid leukemia resistant Quizartinib Preclinical - Cell culture Actionable In a preclinical study, primary patient-derived acute myeloid leukemia blasts harboring FLT3-ITD with FLT3 D835V were less sensitive to Vanflyta (quizartinib) in culture (PMID: 38231480). 38231480
FLT3 N676K hematologic cancer sensitive Foretinib Preclinical - Cell culture Actionable In a preclinical study, Foretinib (GSK1363089) inhibited viability of cultured cells expressing FLT3 N676K (PMID: 38231480). 38231480
FLT3 Y842C hematologic cancer resistant Quizartinib Preclinical - Cell culture Actionable In a preclinical study, cultured cells expressing FLT3 Y842C were resistant to treatment with Vanflyta (quizartinib) (PMID: 38231480). 38231480