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Volume 14
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10.3390/cells14060447
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Article

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

by
Kimio Yonesaka
1,*,
Takashi Kurosaki
1,
Junko Tanizaki
1,2,
Hisato Kawakami
1,
Kaoru Tanaka
1,
Osamu Maenishi
3,
Shiki Takamura
4,
Kazuko Sakai
5,
Yasutaka Chiba
6,
Takeshi Teramura
7,
Hiroki Goto
8,
Eri Otsuka
8,
Hiroaki Okida
8,
Masanori Funabashi
8,
Yuuri Hashimoto
9,
Kenji Hirotani
10,
Yasuki Kamai
11,
Takashi Kagari
11,
Kazuto Nishio
5,
Kazuhiro Kakimi
4 and
Hidetoshi Hayashi
1add Show full author list remove Hide full author list
1
Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka 589-8511, Japan
2
Department of Medical Oncology, Kishiwada City Hospital, Osaka 589-8511, Japan
3
Department of Pathology, Kindai University Faculty of Medicine, Osaka 589-8511, Japan
4
Department of Immunology, Kindai University Faculty of Medicine, Osaka 589-8511, Japan
5
Department of Genome Biology, Kindai University Faculty of Medicine, Osaka 589-8511, Japan
6
Clinical Research Center, Kindai University Hospital, Osaka 589-8511, Japan
7
Division of Cell Biology for Regenerative Medicine, Institute of Advanced Clinical Medicine, Kindai University Faculty of Medicine, Osaka 589-8511, Japan
8
Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo 134-0081, Japan
9
Discovery Intelligence Research Laboratories, Research Function, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 103-0023, Japan
10
Early Clinical Development Department, Development Function, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 103-0023, Japan
11
Discovery Research Laboratories I, Research Function, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 103-0023, Japan
 
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remove Hide full affiliation list
*
Author to whom correspondence should be addressed.
Cells 2025, 14(6), 447; https://doi.org/10.3390/cells14060447
Submission received: 11 February 2025 / Revised: 13 March 2025 / Accepted: 14 March 2025 / Published: 17 March 2025
(This article belongs to the Special Issue Unlocking the Secrets Behind Drug Resistance at the Cellular Level)
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Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard therapies for EGFR-mutated non-small-cell lung cancer (NSCLC); however, their efficacy is inconsistent. Secondary mutations in the EGFR 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 EGFR-mutated NSCLC patients. Furthermore, EGFR-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 EGFR-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 EGFR-mutated NSCLC, resulting in EMT-associated EGFR-TKI resistance.
Keywords: EGFR-mutated non-small-cell lung cancer; epidermal growth factor receptor tyrosine kinase inhibitors; chromosomal instability EGFR-mutated non-small-cell lung cancer; epidermal growth factor receptor tyrosine kinase inhibitors; chromosomal instability
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MDPI and ACS Style

Yonesaka, K.; Kurosaki, T.; Tanizaki, J.; Kawakami, H.; Tanaka, K.; Maenishi, O.; Takamura, S.; Sakai, K.; Chiba, Y.; Teramura, T.; et al. Chromosomal Instability Is Associated with cGAS–STING Activation in EGFR-TKI Refractory Non-Small-Cell Lung Cancer. Cells 2025, 14, 447. https://doi.org/10.3390/cells14060447

AMA Style

Yonesaka K, Kurosaki T, Tanizaki J, Kawakami H, Tanaka K, Maenishi O, Takamura S, Sakai K, Chiba Y, Teramura T, et al. Chromosomal Instability Is Associated with cGAS–STING Activation in EGFR-TKI Refractory Non-Small-Cell Lung Cancer. Cells. 2025; 14(6):447. https://doi.org/10.3390/cells14060447

Chicago/Turabian Style

Yonesaka, Kimio, Takashi Kurosaki, Junko Tanizaki, Hisato Kawakami, Kaoru Tanaka, Osamu Maenishi, Shiki Takamura, Kazuko Sakai, Yasutaka Chiba, Takeshi Teramura, and et al. 2025. "Chromosomal Instability Is Associated with cGAS–STING Activation in EGFR-TKI Refractory Non-Small-Cell Lung Cancer" Cells 14, no. 6: 447. https://doi.org/10.3390/cells14060447

APA Style

Yonesaka, K., Kurosaki, T., Tanizaki, J., Kawakami, H., Tanaka, K., Maenishi, O., Takamura, S., Sakai, K., Chiba, Y., Teramura, T., Goto, H., Otsuka, E., Okida, H., Funabashi, M., Hashimoto, Y., Hirotani, K., Kamai, Y., Kagari, T., Nishio, K., ... Hayashi, H. (2025). Chromosomal Instability Is Associated with cGAS–STING Activation in EGFR-TKI Refractory Non-Small-Cell Lung Cancer. Cells, 14(6), 447. https://doi.org/10.3390/cells14060447

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