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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 PloS one
Vol 14
Issue 12
Date 2019
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
Drug Name Trade Name Synonyms Drug Classes Drug Description
A-419259 RK-20449|RK20449|RK 20449|A 419259|A419259 FLT3 Inhibitor 57 LYN Inhibitor 3 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, Apr 2022). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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
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