Reference Detail

Ref Type

Journal Article

PMID

(12124173)

Authors

Weisberg E, Boulton C, Kelly LM, Manley P, Fabbro D, Meyer T, Gilliland DG, Griffin JD

Title

Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	1	5	2002 Jun	433-43	Cancer Cell

URL

Abstract Text

Constitutively activating FLT3 receptor mutations have been found in 35% of patients with acute myeloblastic leukemia (AML). Here we report the identification of a small molecule FLT3 tyrosine kinase inhibitor PKC412, which selectively induced G1 arrest and apoptosis of Ba/F3 cell lines expressing mutant FLT3 (IC(50) < 10 nM) by directly inhibiting the tyrosine kinase. Ba/F3-FLT3 cell lines made resistant to PKC412 demonstrated overexpression of mutant FLT3, confirming that FLT3 is the target of this drug. Finally, progressive leukemia was prevented in PKC412-treated Balb/c mice transplanted with marrow transduced with a FLT3-ITD-expressing retrovirus. PKC412 is a potent inhibitor of mutant FLT3 and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors.

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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
Midostaurin	Midostaurin	110	13

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Midostaurin	Rydapt	PKC412\|CGP 41251	CSF1R Inhibitor 28 FLT3 Inhibitor 66 KIT Inhibitor 57 PKC alpha Inhibitor 6 PKC beta Inhibitor 6 PKC Inhibitor (Pan) 11 VEGFR2 Inhibitor 37	Rydapt (midostaurin) is a multi-kinase inhibitor with activity against FLT3, KIT, PDGFRB, KDR (VEGFR2) and PKC, with higher selectivity for conventional PKC isoforms, which induces cell cycle arrest and apoptosis (PMID: 12124173, PMID: 23127174, PMID: 15914319). Rydapt (midostaurin) is FDA approved for FLT3-mutant AML in combination with chemotherapy, and is approved for use in aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, or mast cell leukemia as a single therapy (FDA.gov).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 D835Y	Advanced Solid Tumor	sensitive	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with Rydapt (midostaurin) inhibited FLT3 phosphorylation and resulted in decreased proliferation and viability of transformed cells expressing FLT3 D835Y in culture (PMID: 12124173).	12124173
FLT3 exon 14 ins	Advanced Solid Tumor	sensitive	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, Rydapt (midostaurin) demonstrated efficacy in inhibiting proliferation and viability of transformed cells expressing a FLT3-ITD mutation in culture (PMID: 12124173).	12124173
FLT3 wild-type	Advanced Solid Tumor	sensitive	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, Rydapt (midostaurin) inhibited FLT3 phosphorylation in transformed cells expressing wild-type FLT3 in culture (PMID: 12124173).	12124173