Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	64	18	2004 Sep 15	6385-9	Cancer Res

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: 17620426), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Dec 2023).	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, Apr 2024).	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, Oct 2023).	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, Oct 2023).	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
FLT3 exon 14 ins FLT3 A627T	hematologic cancer	predicted - resistant	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing a FLT3-ITD mutation with FLT3 A627T demonstrated moderate resistance to treatment with Rydapt (midostaurin) in culture (PMID: 15374944).	15374944