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Ref Type Journal Article
PMID (15374944)
Authors Cools J, Mentens N, Furet P, Fabbro D, Clark JJ, Griffin JD, Marynen P, Gilliland DG
Title Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia.
Journal Cancer research
Vol 64
Issue 18
Date 2004 Sep 15
URL
Abstract Text Mutations in the receptor tyrosine kinase FLT3 occur frequently in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Small molecules that selectively inhibit FLT3 kinase activity induce apoptosis in blasts from AML patients with FLT3 mutations and prolong survival in animal models of FLT3-induced myeloproliferative disease. A spectrum of structurally different small molecules with activity against FLT3 have been described, and their efficacy for treatment of AML and ALL is now being investigated in clinical trials. Here, we describe the results of an in vitro screen designed to identify mutations in the ATP-binding pocket of FLT3 that confer resistance to tyrosine kinase inhibitors. Mutations at four different positions (Ala-627, Asn-676, Phe-691, and Gly-697) were identified that confer varying degrees of resistance to PKC412, SU5614, or K-252a. FLT3 proteins mutated at Ala-627, Asn-676, or Phe-691 remained sensitive to higher concentrations of the inhibitors, but the G697R mutation conferred high-level resistance to each of these inhibitors as well as to six additional experimental inhibitors. These data provide insights into potential mechanisms of acquired resistance of FLT3 to small molecule inhibitors and indicate that the G697R mutation may be a clinically problematic resistance mutation that warrants proactive screening for additional 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
FLT3 A627T missense unknown FLT3 A627T lies within the protein kinase domain of the Flt3 protein (UniProt.org). A627T has been identified as a drug resistance mutation (PMID: 15374944, PMID: 17229632, PMID: 17620426), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Sep 2021). Y
FLT3 G697R missense unknown FLT3 G697R lies within the protein kinase domain of the Flt3 protein (UniProt.org). G697R has been demonstrated to occur as a secondary resistance mutation in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 15374944, PMID: 22875611, PMID: 17827387), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Sep 2021). Y
FLT3 N676D missense unknown FLT3 N676D lies within the protein kinase domain of the Flt3 protein (UniProt.org). N676D has been demonstrated to occur as a secondary resistance mutation in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 22875611, PMID: 15374944), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Sep 2021). Y
FLT3 N676S missense unknown FLT3 N676S lies within the protein kinase domain of the Flt3 protein (UniProt.org). N676S has been demonstrated to occur as a secondary resistance mutation in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 25847190, PMID: 15374944, PMID: 31790499), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Sep 2021). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 exon 14 ins FLT3 G697R hematologic cancer resistant Midostaurin Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and FLT3 G697R were resistant to Rydapt (midostaurin) in culture (PMID: 15374944). 15374944