Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Science translational medicine	7	291	2015 Jun 10	291ra96	Sci Transl Med

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	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
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