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

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard therapies for <i>EGFR</i>-mutated non-small-cell lung cancer (NSCLC); however, their efficacy is inconsistent. Secondary mutations in the <i>EGFR</i> or other genes that lead to resistance have been identified, but resistance mechanisms have not been fully identified. Chromosomal instability (CIN) is a hallmark of cancer and results in genetic diversity. In this study, we demonstrated by transcriptomic analysis that CIN activates the cGAS-STING signaling pathway, which leads to EGFR-TKI refractoriness in a subset of <i>EGFR</i>-mutated NSCLC patients. Furthermore, <i>EGFR</i>-mutated H1975dnMCAK cells, which frequently underwent chromosomal mis-segregation, demonstrated refractoriness to the EGFR-TKI osimertinib compared to control cells. Second, H1975dnMCAK cells exhibited activation of cGAS-STING signaling and its downstream signaling, including tumor-promoting cytokine IL-6. Finally, chromosomally unstable <i>EGFR</i>-mutated NSCLC exhibited enhanced epithelial-mesenchymal transition (EMT). Blockade of cGAS-STING-TBK1 signaling reversed EMT, resulting in restored susceptibility to EGFR-TKIs in vitro and in vivo. These results suggest that CIN may lead to the activation of cGAS-STING signaling in some <i>EGFR</i>-mutated NSCLC, resulting in EMT-associated EGFR-TKI resistance.