ATM inhibition restores IFN-γ sensitivity and induces ferroptosis in NSCLC via DNA damage response

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Cancer immunotherapy, particularly using Interferon-gamma (IFN-γ), shows promise but faces challenges with patient response rates and resistance.
• Tumor cells often neutralize IFN-γ, limiting its anti-tumor efficacy.
• Understanding mechanisms of IFN-γ resistance is crucial for improving cancer treatment outcomes.

Purpose of the Study:

• To investigate the regulation of IFN-γ responsiveness in non-small cell lung cancer (NSCLC) cell lines.
• To explore the role of the ataxia telangiectasia mutated (ATM) kinase in mediating IFN-γ resistance.
• To identify therapeutic strategies to overcome IFN-γ resistance in NSCLC.

Main Methods:

• Comparative analysis of IFN-γ response in PC-9 and A549 NSCLC cell lines.
• Transcriptomic analysis to identify molecular pathways involved in IFN-γ resistance.
• Pharmacological inhibition of ATM using KU-55933 to assess its impact on IFN-γ sensitivity.
• Assessment of DNA damage response, glutathione metabolism, and ferroptosis induction.

Main Results:

• PC-9 cells exhibited higher resistance to IFN-γ compared to A549 cells.
• IFN-γ-resistant cells showed enrichment in homologous recombination (HR) DNA repair pathway genes.
• ATM inhibition restored IFN-γ sensitivity by inducing ferroptosis in NSCLC cells.
• Combined IFN-γ treatment and ATM inhibition triggered DNA damage, disrupted glutathione metabolism, and promoted ferroptosis.

Conclusions:

• The ataxia telangiectasia mutated (ATM) pathway plays a significant role in mediating resistance to Interferon-gamma (IFN-γ) in non-small cell lung cancer (NSCLC).
• Inhibition of ATM can re-sensitize NSCLC cells to IFN-γ, leading to ferroptosis induction.
• Targeting DNA damage response pathways, such as ATM, presents a potential strategy to enhance the efficacy of cancer immunotherapy.