What question did this study set out to answer?

Investigate how ATRX-IFF mutations contribute to chemoresistance in neuroblastoma and identify targetable proteins.

April 5, 2026Cancer Research0 citations

Abstract 2995: ATRX in-frame fusions promote endogenous chemoresistance programs but yield immunotherapeutic vulnerabilities in neuroblastoma

MNMohammad Ali Mohammad Nezhady SBSheetal Bhatara SHSiarhei Hladyshau

Key Points

Investigate how ATRX-IFF mutations contribute to chemoresistance in neuroblastoma and identify targetable proteins.
Used single-cell RNA sequencing (scRNAseq) with cisplatin treatment
Engineered ATRX-IFF into wildtype cells using CRISPR
Conducted chromatin binding assays and cell surface proteomics
Applied findings in cell lines and orthotopic patient-derived xenografts (PDXs)
ATRX-IFF NBs show inherent chemoresistance programs without transcriptionally plastic subpopulations
CRISPR engineering confirms increased chemoresistance to various agents
Identification of PTK7 as a targetable protein with high expression in ATRX-IFF NBs

Abstract

Abstract High-risk Neuroblastomas (NB) carrying in-frame fusion mutations in the ATRX chromatin remodeler(“ATRX-IFF”) are chemoresistant, and children with these mutations display poor overall survival. There are no specific agents to target these tumors, and the mechanisms driving chemoresistance remain unknown. To gain insight into the mechanisms of chemoresistance, we used scRNAseq in combination with cisplatin to study if cellular plasticity drives chemoresistance. In contrast to non-ATRX-IFF-bearing NBs, ATRX-IFF NBs did not appear to display transcriptionally plastic subpopulations, suggesting that the ATRX-IFF promotes an inherent chemoresistance program. To this end, CRISPR-mediated engineering of ATRX-IFF into the endogenous locus in wildtype cells, results in enhanced chemoresistance to multiple clinically-used agents. Next, to identify potential targetable proteins directly regulated by the ATRX-IFF, we combined chromatin binding assays with cell surface proteomics. Using cell lines and orthotopic PDXs, we identified that the ATRX-IFF binds to, and nucleates a super-enhancer at the PTK7 locus, thereby driving extremely high level cell surface expression of PTK7. PTK7 is a pseudokinase receptor that is targeted by experimental CAR-T cell therapies in active preclinical development. Ongoing work is aimed at understanding the dependency of PTK7 on the ATRX-IFF, and using preclinical CAR-T cell models to target PTK7 in ATRX-IFF NB. Citation Format: Mohammad Ali Mohammad Nezhady, Sheetal Bhatara, Siarhei Hladyshau, Estevez Prado Daniel, Vernon Ebegboni, Alja Kozulic-Pirher, Arnav Barpujari, Bo Wang, Yuan Feng, Qiqi Jin, Xueying Liu, Paul Geeleher, Xiaotu Ma, Jiyang Yu, Emily Bernstein, Kelly Goldsmith, Hunter Jonus, Adam D. Durbin. ATRX in-frame fusions promote endogenous chemoresistance programs but yield immunotherapeutic vulnerabilities in neuroblastoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2995.

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