Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell			2019 Oct 09	512-527.e9	Cancer Cell

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	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
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	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