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Ref Type Journal Article
PMID (17827387)
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.
Journal Blood
Vol 110
Issue 13
Date 2007 Dec 15
URL
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.

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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 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