Novel, clinically relevant genomic patterns identified by comprehensive genomic profiling in ATRX-deficient IDH-wildtype adult high-grade gliomas

Bedics, Gábor; Szőke, Péter; Bátai, Bence; Nagy, Tibor; Papp, Gergő; Kránitz, Noémi; Rajnai, Hajnalka; Reiniger, Lilla; Bödör, Csaba; Scheich, Bálint

doi:10.1038/s41598-023-45786-w

Cited by 2 publications

(1 citation statement)

References 57 publications

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“…It has been implicated in various pathways involved in the DNA damage response (DDR), including the replication stress response [17][18][19], homologous recombination (HR) [20,21], and nonhomologous end joining (NHEJ) [22]. Genomic profiling of ATRX-deficient adult high-grade gliomas revealed the genetic characteristics of homologous recombination repair [23]. ATRX plays a critical role in double-stranded break (DSB) repair [22].…”

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confidence: 99%

Knockdown of ATRX enhances radiosensitivity in glioblastoma

Zhao,

Chen,

Liu

et al. 2024

Chin Neurosurg Jl

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Background Glioblastoma are highly malignant type of primary brain tumors. Treatment for glioblastoma multiforme (GBM) generally involves surgery combined with chemotherapy and radiotherapy. However, the development of tumoral chemo- and radioresistance induces complexities in clinical practice. Multiple signaling pathways are known to be involved in radiation-induced cell survival. However, the role of alpha-thalassemia X-linked mutant retardation syndrome (ATRX), a chromatin remodeling protein, in GBM radioresistance remains unclear. Methods In the present study, the ATRX mutation rate in patients with glioma was obtained from The Cancer Genome Atlas, while its expression analyzed using bioinformatics. Datasets were also obtained from the Gene Expression Omnibus, and ATRX expression levels following irradiation of GBM were determined. The effects of ATRX on radiosensitivity were investigated using a knockdown assays. Results The present study demonstrated that the ATRX mutation rate in patients with GBM was significantly lower than that in patients with low-grade glioma, and that patients harboring an ATRX mutation exhibited a prolonged survival, compared with to those harboring the wild-type gene. Single-cell RNA sequencing demonstrated that ATRX counts increased 2 days after irradiation, with ATRX expression levels also increasing in U-251MG radioresistant cells. Moreover, the results of in vitro irradiation assays revealed that ATRX expression was increased in U-251MG cells, while ATRX knockdown was associated with increased levels of radiosensitivity. Conclusions High ATRX expression levels in primary GBM may contribute to high levels of radioresistance. Thus ATRX is a potential target for overcoming the radioresistance in GBM.

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confidence: 99%

Knockdown of ATRX enhances radiosensitivity in glioblastoma

Zhao,

Chen,

Liu

et al. 2024

Chin Neurosurg Jl

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High-Throughput Targeted Drug Screening for NF1-associated High-Grade Gliomas with ATRX Deficiency

Dubey,

Rai,

Guillen

et al. 2024

Preprint

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Neurofibromatosis type 1 (NF1)-associated high-grade gliomas (HGGs) harboring ATRX mutations exhibit an aggressive clinical phenotype, driven by heightened genomic instability and metabolic reprogramming. Existing therapies, including chemotherapy and radiotherapy, are limited by resistance mechanisms and formation of secondary malignancy, underscoring the need for novel therapeutic strategies. Here, we report the results of a high-throughput screening of 10,000 small molecules aimed at identifying compounds selectively targeting vulnerabilities associated with concurrent ATRX and NF1 loss. Among the screened compounds, K784-6195 (ChemDiv ID) emerged as a promising candidate, exhibiting marked selective cytotoxicity in NF1-associated glioma cell lines with ATRX deficiency (IC50 = 4.84 µM). In comparison, wild-type ATRX sporadic glioma cell lines (U251) exhibited significantly reduced sensitivity to K784-6195 (IC50 = 37.03 µM). However, ATRX knockout U251 glioma cells recapitulating concurrent ATRX and NF1 loss exhibited heightened susceptibility to K784-6195 (IC50 = 20-23 µM) compared to their wild-type counterpart. Metabolomic analysis revealed that K784-6195 treatment impairs metabolic pathways, including the pentose phosphate pathway, glutamine metabolism, and redox homeostasis, leading to oxidative stress and impaired cell survival. These findings highlight K784-6195 as a promising candidate for therapeutic development, offering a targeted approach for the treatment of NF-1 associated HGGs with ATRX deficiency.

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Novel, clinically relevant genomic patterns identified by comprehensive genomic profiling in ATRX-deficient IDH-wildtype adult high-grade gliomas

Cited by 2 publications

References 57 publications

Knockdown of ATRX enhances radiosensitivity in glioblastoma

Knockdown of ATRX enhances radiosensitivity in glioblastoma

High-Throughput Targeted Drug Screening for NF1-associated High-Grade Gliomas with ATRX Deficiency

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