Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

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 Leukemia
Vol 27
Issue 1
Date 2013 Jan
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.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

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, Jul 2020). 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, Jul 2020). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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 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 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 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 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 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 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
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 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 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