Reference Detail

Ref Type

Journal Article

PMID

(31790499)

Authors

Patel RK, Weir MC, Shen K, Snyder D, Cooper VS, Smithgall TE

Title

Expression of myeloid Src-family kinases is associated with poor prognosis in AML and influences Flt3-ITD kinase inhibitor acquired resistance.

Journal	Vol	Issue	Date	Pages	Journal Short Title
PloS one	14	12	2019	e0225887	PLoS One

URL

Abstract Text

Unregulated protein-tyrosine kinase signaling is a common feature of AML, often involving mutations in Flt3 and overexpression of myeloid Src-family kinases (Hck, Fgr, Lyn). Here we show that high-level expression of these Src kinases predicts poor survival in a large cohort of AML patients. To test the therapeutic benefit of Flt3 and Src-family kinase inhibition, we used the pyrrolopyrimidine kinase inhibitor A-419259. This compound potently inhibits Hck, Fgr, and Lyn as well as Flt3 bearing an activating internal tandem duplication (ITD). Flt3-ITD expression sensitized human TF-1 myeloid cells to growth arrest by A-419259, supporting direct action on the Flt3-ITD kinase domain. Cells transformed with the Flt3-ITD mutants D835Y and F691L were resistant to A-419259, while co-expression of Hck or Fgr restored inhibitor sensitivity to Flt3-ITD D835Y. Conversely, Hck and Fgr mutants with engineered A-419259 resistance mutations decreased sensitivity of TF-1/Flt3-ITD cells. To investigate de novo resistance mechanisms, A-419259-resistant Flt3-ITD+ AML cell populations were derived via long-term dose escalation. Whole exome sequencing identified a distinct Flt3-ITD kinase domain mutation (N676S/T) among all A-419259 target kinases in each of six independent resistant cell populations. These studies show that Hck and Fgr expression influences inhibitor sensitivity and the pathway to acquired resistance in Flt3-ITD+ 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
A-419259	A-419259	5	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
A-419259		RK-20449\|RK20449\|RK 20449\|A 419259\|A419259	FLT3 Inhibitor 69 LYN Inhibitor 4	A-419259 is an multi-kinase inhibitor with activity against Src family of kinases, including Hck, Fgr, Lyn, Flt3, and wild-type FLT3-ITD, potentially resulting in reduced viability of tumor cells (PMID: 31790499).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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, May 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins	myeloid leukemia	sensitive	A-419259	Preclinical - Cell culture	Actionable	In a preclinical study, transformed myeloid leukemia cells expressing FLT3-ITD were sensitive to treatment with A-419259, demonstrating inhibition of cell growth in culture (PMID: 31790499).	31790499
FLT3 exon 14 ins FLT3 F691L	myeloid leukemia	resistant	A-419259	Preclinical - Cell culture	Actionable	In a preclinical study, transformed myeloid leukemia cells co-expressing FLT-ITD and FLT3 F691L demonstrated resistance to A-419259 treatment in culture (PMID: 31790499).	31790499
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	A-419259	Preclinical - Cell culture	Actionable	In a preclinical study, A-419259 treatment inhibited viability of an acute myeloid leukemia cell line harboring FLT3-ITD in culture (PMID: 31790499).	31790499
FLT3 exon 14 ins FLT3 D835Y	myeloid leukemia	resistant	A-419259	Preclinical - Cell culture	Actionable	In a preclinical study, transformed myeloid leukemia cells co-expressing FLT-ITD and FLT3 D835Y demonstrated resistance to A-419259 treatment in culture (PMID: 31790499).	31790499
FLT3 exon 14 ins FLT3 N676S	myeloid leukemia	resistant	A-419259	Preclinical - Cell culture	Actionable	In a preclinical study, transformed myeloid leukemia cells co-expressing FLT-ITD and FLT3 N676S demonstrated resistance to A-419259 treatment in culture (PMID: 31790499).	31790499