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Ref Type Journal Article
PMID (26062848)
Authors Lim Y, Gondek L, Li L, Wang Q, Ma H, Ma H, Chang E, Huso DL, Foerster S, Marchionni L, McGovern K, Watkins DN, Peacock CD, Levis M, Smith BD, Merchant AA, Small D, Matsui W
Title Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia.
Journal Science translational medicine
Vol 7
Issue 291
Date 2015 Jun 10
URL
Abstract Text FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations resulting in constitutive kinase activity are common in acute myeloid leukemia (AML) and carry a poor prognosis. Several agents targeting FLT3 have been developed, but their limited clinical activity suggests that the inhibition of other factors contributing to the malignant phenotype is required. We examined gene expression data sets as well as primary specimens and found that the expression of GLI2, a major effector of the Hedgehog (Hh) signaling pathway, was increased in FLT3-ITD compared to wild-type FLT3 AML. To examine the functional role of the Hh pathway, we studied mice in which Flt3-ITD expression results in an indolent myeloproliferative state and found that constitutive Hh signaling accelerated the development of AML by enhancing signal transducer and activator of transcription 5 (STAT5) signaling and the proliferation of bone marrow myeloid progenitors. Furthermore, combined FLT3 and Hh pathway inhibition limited leukemic growth in vitro and in vivo, and this approach may serve as a therapeutic strategy for 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
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 exon 14 ins acute myeloid leukemia sensitive Saridegib + Sorafenib Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of Nexavar (sorafenib) and Saridegib (IPI-926) resulted in significantly decreased cell proliferation compared to Nexavar (sorafenib) alone in two acute myeloid leukemia cell lines harboring FLT3-ITD mutations in culture (PMID: 26062848). 26062848
FLT3 exon 14 ins acute myeloid leukemia sensitive Sonidegib + Sorafenib Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of Nexavar (sorafenib) and Odomzo (sonidegib) resulted in significantly decreased cell proliferation compared to Nexavar (sorafenib) alone in an acute myeloid leukemia cell line harboring a FLT3-ITD mutation in culture (PMID: 26062848). 26062848