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Ref Type Journal Article
PMID (35395091)
Authors Ferng TT, Terada D, Ando M, Tarver TC, Chaudhary F, Lin KC, Logan AC, Smith CC
Title The Irreversible FLT3 Inhibitor FF-10101 Is Active Against a Diversity of FLT3 Inhibitor Resistance Mechanisms.
Journal Molecular cancer therapeutics
Vol 21
Issue 5
Date 2022 May 04
URL
Abstract Text Small-molecule FLT3 inhibitors have recently improved clinical outcomes for patients with FLT3-mutant acute myeloid leukemia (AML) after many years of development, but resistance remains an important clinical problem. FF-10101 is the first irreversible, covalent inhibitor of FLT3 which has previously shown activity against FLT3 tyrosine kinase inhibitor resistance-causing FLT3 F691L and D835 mutations. We report that FF-10101 is also active against an expanded panel of clinically identified FLT3 mutations associated with resistance to other FLT3 inhibitors. We also demonstrate that FF-10101 can potentially address resistance mechanisms associated with growth factors present in the bone marrow microenvironment but is vulnerable to mutation at C695, the amino acid required for covalent FLT3 binding. These data suggest that FF-10101 possesses a favorable resistance profile that may contribute to improved single-agent efficacy when used in patients with FLT3-mutant AML.

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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
FLT3 G697S missense unknown FLT3 G697S lies within the protein kinase domain of the Flt3 protein (UniProt.org). G697S has been demonstrated to promote secondary drug resistance in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 35395091), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, May 2022). Y
FLT3 Y693C missense unknown FLT3 Y693C lies within the protein kinase domain of the Flt3 protein (UniProt.org). Y693C has been demonstrated to promote secondary drug resistance in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 32040554, PMID: 35395091), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, May 2022). Y
FLT3 Y693F missense unknown FLT3 Y693F lies within the protein kinase domain of the Flt3 protein (UniProt.org). Y693F has been identified in the scientific literature (PMID: 35395091), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, May 2022).
FLT3 Y693N missense unknown FLT3 Y693N lies within the protein kinase domain of the Flt3 protein (UniProt.org). Y693N has been demonstrated to promote secondary drug resistance in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 32040554, PMID: 35395091), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, May 2022). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 exon 14 ins FLT3 C807S hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 C807S in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 Y693C Advanced Solid Tumor resistant FF-10101 Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3-ITD and FLT3 Y693C were resistant to treatment with FF-10101 in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 N676K hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 N676K in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 C695S hematologic cancer predicted - resistant FF-10101 Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3-ITD and FLT3 C695S were resistant to treatment with FF-10101 in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 D835A hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 D835A in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 D835I hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 D835I in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 D835E hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 D835E in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 F691L FLT3 D835V hematologic cancer predicted - resistant FF-10101 Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3-ITD with FLT3 F691L and D835V were moderately resistant to treatment with FF-10101 in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 K429E hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 K429E in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 G697S Advanced Solid Tumor predicted - resistant FF-10101 Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3-ITD and FLT3 G697S were moderately resistant to treatment with FF-10101 in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 C694S hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 C694S in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 Y693F hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 Y693F in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 D835G hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 D835G in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 D698N FLT3 D835V hematologic cancer predicted - resistant FF-10101 Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3-ITD with FLT3 D698N and D835V were moderately resistant to treatment with FF-10101 in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 D698N hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 D698N in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 Y693N Advanced Solid Tumor predicted - resistant FF-10101 Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3-ITD and FLT3 Y693N were moderately resistant to treatment with FF-10101 in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 C681S hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 C681S in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 D835F hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 D835F in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 C828S hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 C828S in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 D835N hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 D835N in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 D835Y hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 D835Y in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 Y693C FLT3 D835V hematologic cancer resistant FF-10101 Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3-ITD with FLT3 Y693C and D835V were resistant to treatment with FF-10101 in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 D835del hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 D835del in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 C790S hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 C790S in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins Advanced Solid Tumor sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 D835H hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 D835H in culture (PMID: 35395091). 35395091
FLT3 exon 14 ins FLT3 D835V hematologic cancer sensitive FF-10101 Preclinical - Cell culture Actionable In a preclinical study, FF-10101 treatment inhibited growth of transformed hematologic cells expressing FLT3-ITD and FLT3 D835V in culture (PMID: 35395091). 35395091