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Ref Type Journal Article
PMID (31631027)
Authors Qadeer ZA, Valle-Garcia D, Hasson D, Sun Z, Cook A, Nguyen C, Soriano A, Ma A, Griffiths LM, Zeineldin M, Filipescu D, Jubierre L, Chowdhury A, Deevy O, Chen X, Finkelstein DB, Bahrami A, Stewart E, Federico S, Gallego S, Dekio F, Fowkes M, Meni D, Maris JM, Weiss WA, Roberts SS, Cheung NV, Jin J, Segura MF, Dyer MA, Bernstein E
Title ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures.
Journal Cancer cell
Vol
Issue
Date 2019 Oct 09
URL
Abstract Text ATRX alterations occur at high frequency in neuroblastoma of adolescents and young adults. Particularly intriguing are the large N-terminal deletions of ATRX (Alpha Thalassemia/Mental Retardation, X-linked) that generate in-frame fusion (IFF) proteins devoid of key chromatin interaction domains, while retaining the SWI/SNF-like helicase region. We demonstrate that ATRX IFF proteins are redistributed from H3K9me3-enriched chromatin to promoters of active genes and identify REST as an ATRX IFF target whose activation promotes silencing of neuronal differentiation genes. We further show that ATRX IFF cells display sensitivity to EZH2 inhibitors, due to derepression of neurogenesis genes, including a subset of REST targets. Taken together, we demonstrate that ATRX structural alterations are not loss-of-function and put forward EZH2 inhibitors as a potential therapy for ATRX IFF neuroblastoma.

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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
ATRX fusion neuroblastoma predicted - sensitive Tazemetostat Preclinical - Cell culture Actionable In a preclinical study, treatment with Tazemetostat (EPZ-6438) resulted in reduced proliferation and increased apoptosis of neuroblastoma cell lines harboring in-frame ATRX fusions in culture (PMID: 31631027). 31631027
ATRX fusion neuroblastoma predicted - sensitive GSK126 Preclinical - Cell culture Actionable In a preclinical study, treatment with GSK126 resulted in reduced proliferation and increased apoptosis of neuroblastoma cell lines harboring in-frame ATRX fusions in culture (PMID: 31631027). 31631027
ATRX fusion neuroblastoma predicted - sensitive UNC1999 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with UNC1999 resulted in reduced proliferation and increased apoptosis of neuroblastoma cell lines harboring in-frame ATRX fusions in culture, and decreased tumor growth in a neuroblastoma cell line xenograft model harboring an ATRX fusion (PMID: 31631027). 31631027