cGAS-STING signal status after EGFR-TKIs resistance in Non-Small Cell Lung Cancer

Fang Hao^*

• Tianjin Medical University General Hospital, Tianjin, China

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have propelled a targeted therapeutic paradigm for non-small cell lung cancer (NSCLC). 3 rd generation EGFR-TKIs, such as osimertinib and almonertinib, became the standard of care based on overall survival benefit over 1 st and 2 nd generation TKIs. Nevertheless, a small subpopulation of cells within NSCLC survives initial treatment and ultimately drives tumor relapse and acquired resistance. Although mutations in cGAS-stimulator of interferon genes (STING) signaling components are rarely observed in tumors, epigenetic dysregulation represents a distinct event, highlighting its role in immunosurveillance during tumor initiation and propagation. EGFR activation facilitates DNA damage and persistent "insults" after TKI administration enable cells evade DNA damage response (DDR) and cGAS-STING signaling to promote survival. cGAS-STING dysfunction is not merely a consequence of acquired resistance but a prerequisite for malignant progression, reprogramming tumor-initiating cells into therapy-resistant cancer stem cells. Herein, we summarized studies on NSCLC progression following a cascade of initial DNA damage and focuses on synergistic regulation between cGAS/STING and compensatory signaling networks post-TKI treatment.