Chromosomal Instability Is Associated with cGAS-STING Activation in EGFR-TKI Refractory Non-Small-Cell Lung Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are crucial for EGFR-mutated non-small-cell lung cancer (NSCLC).
• However, inconsistent efficacy and acquired resistance limit their long-term benefit.
• Mechanisms of resistance, beyond secondary mutations, remain incompletely understood.

Purpose of the Study:

• To investigate the role of chromosomal instability (CIN) in mediating resistance to EGFR-TKIs in NSCLC.
• To elucidate the molecular pathways linking CIN to EGFR-TKI refractoriness.
• To explore therapeutic strategies targeting CIN-induced resistance.

Main Methods:

• Transcriptomic analysis to identify pathways activated by CIN.
• Cellular models of CIN (H1975dnMCAK cells) to assess EGFR-TKI response.
• Evaluation of cGAS-STING signaling activation and downstream effects (e.g., IL-6).
• Assessment of epithelial-mesenchymal transition (EMT) in chromosomally unstable NSCLC.
• In vitro and in vivo experiments to test blockade of cGAS-STING-TBK1 signaling.

Main Results:

• CIN was found to activate the cGAS-STING signaling pathway in a subset of EGFR-mutated NSCLC.
• H1975dnMCAK cells with CIN showed refractoriness to osimertinib, linked to activated cGAS-STING and IL-6 signaling.
• Chromosomally unstable NSCLC exhibited enhanced EMT.
• Inhibition of cGAS-STING-TBK1 signaling reversed EMT and restored sensitivity to EGFR-TKIs.

Conclusions:

• Chromosomal instability may drive EGFR-TKI resistance in some NSCLC patients via cGAS-STING pathway activation.
• This pathway activation promotes EMT, contributing to treatment refractoriness.
• Targeting the cGAS-STING-TBK1 axis offers a potential strategy to overcome EGFR-TKI resistance in CIN-positive NSCLC.