Reference Detail

Ref Type

Journal Article

PMID

(22858906)

Authors

Williams AB, Nguyen B, Li L, Brown P, Levis M, Leahy D, Small D

Title

Mutations of FLT3/ITD confer resistance to multiple tyrosine kinase inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Leukemia	27	1	2013 Jan	48-55	Leukemia

URL

Abstract Text

FMS-like tyrosine kinase 3 (FLT3) normally functions in the survival/proliferation of hematopoietic stem/progenitor cells, but its constitutive activation by internal tandem duplication (ITD) mutations correlates with a poor prognosis in AML. The development of FLT3 tyrosine kinase inhibitors (TKI) is a promising strategy, but resistance that arises during the course of treatment caused by secondary mutations within the mutated gene itself poses a significant challenge. In an effort to predict FLT3 resistance mutations that might develop in patients, we used saturation mutagenesis of FLT3/ITD followed by selection of transfected cells in FLT3 TKI. We identified F621L, A627P, F691L and Y842C mutations in FLT3/ITD that confer varying levels of resistance to FLT3 TKI. Western blotting confirmed that some FLT3 TKI were ineffective at inhibiting FLT3 autophosphorylation and signaling through MAP kinase, STAT5 and AKT in some mutants. Balb/c mice transplanted with the FLT3/ITD Y842C mutation confirmed resistance to sorafenib in vivo but not to lestaurtinib. These results indicate a growing number of FLT3 mutations that are likely to be encountered in patients. Such knowledge, combined with known remaining sensitivity to other FLT3 TKI, will be important to establish as secondary drug treatments that can be substituted when these mutants are encountered.

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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	A627P	missense	unknown	FLT3 A627P lies within the protein kinase domain of the Flt3 protein (UniProt.org). A627P has been demonstrated to confer resistance to FLT3 inhibitors (PMID: 22858906), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Apr 2024).	Y
FLT3	F621L	missense	unknown	FLT3 F621L lies within the protein kinase domain of the Flt3 protein (UniProt.org). F621L has been identified in the scientific literature (PMID: 22858906), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Apr 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins FLT3 Y842C	hematologic cancer	resistant	KW-2449	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells co-expressing FLT3 ITD and FLT3 Y842C were resistant to treatment with KW-2449 in culture (PMID: 22858906).	22858906
FLT3 exon 14 ins FLT3 F621L	hematologic cancer	sensitive	Quizartinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells co-expressing FLT3 ITD and FLT3 F621L were sensitive to treatment with Vanflyta (quizartinib), demonstrating growth inhibition in culture (PMID: 22858906).	22858906
FLT3 exon 14 ins FLT3 A627P	hematologic cancer	resistant	Sorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells co-expressing FLT3 ITD and FLT3 A627P were resistant to treatment with Nexavar (sorafenib) in culture (PMID: 22858906).	22858906
FLT3 exon 14 ins FLT3 F691L	hematologic cancer	resistant	KW-2449	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells co-expressing FLT3 ITD and FLT3 F691L were resistant to treatment with KW-2449 in culture (PMID: 22858906).	22858906
FLT3 exon 14 ins FLT3 F621L	hematologic cancer	resistant	KW-2449	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells co-expressing FLT3 ITD and FLT3 F621L were resistant to treatment with KW-2449 in culture (PMID: 22858906).	22858906
FLT3 exon 14 ins FLT3 A627P	hematologic cancer	resistant	Quizartinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells co-expressing FLT3 ITD and FLT3 A627P were resistant to treatment with Vanflyta (quizartinib) in culture (PMID: 22858906).	22858906
FLT3 exon 14 ins FLT3 A627P	hematologic cancer	resistant	Lestaurtinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells co-expressing FLT3 ITD and FLT3 A627P were resistant to treatment with Lestaurtinib (CEP-701) in culture (PMID: 22858906).	22858906
FLT3 exon 14 ins FLT3 Y842C	hematologic cancer	resistant	Quizartinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells co-expressing FLT3 ITD and FLT3 Y842C were resistant to treatment with Vanflyta (quizartinib) in culture (PMID: 22858906).	22858906
FLT3 exon 14 ins FLT3 A627P	hematologic cancer	resistant	KW-2449	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells co-expressing FLT3 ITD and FLT3 A627P were resistant to treatment with KW-2449 in culture (PMID: 22858906).	22858906
FLT3 exon 14 ins FLT3 A627P	hematologic cancer	resistant	Sunitinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells co-expressing FLT3 ITD and FLT3 A627P were resistant to treatment with Sutent (sunitinib) in culture (PMID: 22858906).	22858906
FLT3 exon 14 ins	hematologic cancer	sensitive	KW-2449	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells expressing FLT3-ITD were sensitive to treatment with KW-2449, demonstrating growth inhibition in culture (PMID: 22858906).	22858906
FLT3 exon 14 ins FLT3 A627P	hematologic cancer	resistant	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells co-expressing FLT3 ITD and FLT3 A627P were resistant to treatment with Rydapt (midostaurin) in culture (PMID: 22858906).	22858906