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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Neurofibromatosis type 1 (NF1)-associated high-grade gliomas (HGGs) with ATRX mutations are aggressive, driven by genomic instability and metabolic reprogramming.
• Current treatments like chemotherapy and radiotherapy have limited efficacy due to resistance and secondary malignancy risks.
• There is a critical need for novel therapeutic strategies targeting the specific vulnerabilities of these tumors.

Purpose of the Study:

• To identify small molecules that selectively target the vulnerabilities of concurrent ATRX and NF1 loss in HGGs.
• To evaluate the efficacy and mechanism of action of promising candidate compounds.

Main Methods:

• A high-throughput screening of 10,000 small molecules was performed.
• Selective cytotoxicity was assessed in NF1-associated glioma cell lines with and without ATRX deficiency.
• Metabolomic analysis was used to investigate the drug's mechanism of action.

Main Results:

• K784-6195 demonstrated marked selective cytotoxicity against NF1-associated glioma cell lines with ATRX deficiency (IC50 = 4.84 μM).
• Wild-type ATRX glioma cells showed significantly reduced sensitivity (IC50 = 37.03 μM), while ATRX knockout cells mimicking concurrent NF1/ATRX loss were more susceptible (IC50 = 20-23 μM).
• K784-6195 treatment impaired the pentose phosphate pathway, glutamine metabolism, and redox homeostasis, inducing oxidative stress and reducing cell survival.

Conclusions:

• K784-6195 is a promising therapeutic candidate for NF1-associated HGGs with ATRX deficiency.
• The compound offers a targeted approach by disrupting critical metabolic pathways essential for tumor cell survival.
• Further development of K784-6195 could lead to a novel treatment for this aggressive form of brain cancer.