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|Ref Type||Journal Article|
|Authors||Barry EV, Clark JJ, Cools J, Roesel J, Gilliland DG|
|Title||Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurin.|
|Date||2007 Dec 15|
|Abstract Text||Small molecule inhibitors that target fms-like tyrosine kinase 3 (FLT3)-activating mutations have potential in the treatment of leukemias. However, certain mutations can simultaneously activate the tyrosine kinase, and confer resistance to small molecule inhibitors. We therefore tested the sensitivity of 8 FLT3 activation loop mutants to midostaurin. Each mutant conferred IL-3 factor-independent proliferation to Ba/F3 cells, and each resulted in the constitutive activation of FLT3 and its targets, signal transducer and activator of transcription 5 (STAT5) and extracellular stimuli-responsive kinase (ERK). For each mutant tested, midostaurin inhibited cell growth and phosphorylation of FLT3, STAT5, and ERK. In contrast, midostaruin did not inhibit Ba/F3 cells stably transduced with FLT3-internal tandem duplications containing a G697R mutation that confers resistance to midostaurin, demonstrating that midostaurin inhibition of FLT3 activation loop mutants was not due to off-target effects. We conclude that midostaurin is a potent inhibitor of a spectrum of FLT3 activation loop mutations, and that acute myeloid leukemia patients with such mutations are potential candidates for clinical trials involving midostaurin.|
|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||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, Sep 2021).||Y|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FLT3 I836del||cancer||sensitive||Midostaurin||Preclinical - Cell culture||Actionable||In a preclinical study, Rydapt (midostaurin) inhibited phosphorylation of FLT3, ERK, and STAT5, and growth of transformed cells expressing FLT3 I836del in culture (PMID: 17827387).||17827387|