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

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 ha...

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Main Authors: Kimio Yonesaka, Takashi Kurosaki, Junko Tanizaki, Hisato Kawakami, Kaoru Tanaka, Osamu Maenishi, Shiki Takamura, Kazuko Sakai, Yasutaka Chiba, Takeshi Teramura, Hiroki Goto, Eri Otsuka, Hiroaki Okida, Masanori Funabashi, Yuuri Hashimoto, Kenji Hirotani, Yasuki Kamai, Takashi Kagari, Kazuto Nishio, Kazuhiro Kakimi, Hidetoshi Hayashi
Format: Article
Language:English
Published: MDPI AG 2025-03-01
Series:Cells
Subjects:
EGFR-mutated non-small-cell lung cancer
epidermal growth factor receptor tyrosine kinase inhibitors
chromosomal instability
Online Access:https://www.mdpi.com/2073-4409/14/6/447
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Summary: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.
ISSN:2073-4409

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