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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2025-03-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Kimio Yonesaka |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0c647d1a6e104baaac992259b3c87079 |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-0c647d1a6e104baaac992259b3c870792025-08-20T03:43:15ZengMDPI AGCells2073-44092025-03-0114644710.3390/cells14060447Chromosomal Instability Is Associated with cGAS–STING Activation in EGFR-TKI Refractory Non-Small-Cell Lung CancerKimio Yonesaka0Takashi Kurosaki1Junko Tanizaki2Hisato Kawakami3Kaoru Tanaka4Osamu Maenishi5Shiki Takamura6Kazuko Sakai7Yasutaka Chiba8Takeshi Teramura9Hiroki Goto10Eri Otsuka11Hiroaki Okida12Masanori Funabashi13Yuuri Hashimoto14Kenji Hirotani15Yasuki Kamai16Takashi Kagari17Kazuto Nishio18Kazuhiro Kakimi19Hidetoshi Hayashi20Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka 589-8511, JapanDepartment of Medical Oncology, Kindai University Faculty of Medicine, Osaka 589-8511, JapanDepartment of Medical Oncology, Kindai University Faculty of Medicine, Osaka 589-8511, JapanDepartment of Medical Oncology, Kindai University Faculty of Medicine, Osaka 589-8511, JapanDepartment of Medical Oncology, Kindai University Faculty of Medicine, Osaka 589-8511, JapanDepartment of Pathology, Kindai University Faculty of Medicine, Osaka 589-8511, JapanDepartment of Immunology, Kindai University Faculty of Medicine, Osaka 589-8511, JapanDepartment of Genome Biology, Kindai University Faculty of Medicine, Osaka 589-8511, JapanClinical Research Center, Kindai University Hospital, Osaka 589-8511, JapanDivision of Cell Biology for Regenerative Medicine, Institute of Advanced Clinical Medicine, Kindai University Faculty of Medicine, Osaka 589-8511, JapanTranslational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo 134-0081, JapanTranslational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo 134-0081, JapanTranslational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo 134-0081, JapanTranslational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo 134-0081, JapanDiscovery Intelligence Research Laboratories, Research Function, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 103-0023, JapanEarly Clinical Development Department, Development Function, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 103-0023, JapanDiscovery Research Laboratories I, Research Function, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 103-0023, JapanDiscovery Research Laboratories I, Research Function, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 103-0023, JapanDepartment of Genome Biology, Kindai University Faculty of Medicine, Osaka 589-8511, JapanDepartment of Immunology, Kindai University Faculty of Medicine, Osaka 589-8511, JapanDepartment of Medical Oncology, Kindai University Faculty of Medicine, Osaka 589-8511, JapanEpidermal 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.https://www.mdpi.com/2073-4409/14/6/447EGFR-mutated non-small-cell lung cancerepidermal growth factor receptor tyrosine kinase inhibitorschromosomal instability |
| spellingShingle | 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 Chromosomal Instability Is Associated with cGAS–STING Activation in EGFR-TKI Refractory Non-Small-Cell Lung Cancer Cells EGFR-mutated non-small-cell lung cancer epidermal growth factor receptor tyrosine kinase inhibitors chromosomal instability |
| title | Chromosomal Instability Is Associated with cGAS–STING Activation in EGFR-TKI Refractory Non-Small-Cell Lung Cancer |
| title_full | Chromosomal Instability Is Associated with cGAS–STING Activation in EGFR-TKI Refractory Non-Small-Cell Lung Cancer |
| title_fullStr | Chromosomal Instability Is Associated with cGAS–STING Activation in EGFR-TKI Refractory Non-Small-Cell Lung Cancer |
| title_full_unstemmed | Chromosomal Instability Is Associated with cGAS–STING Activation in EGFR-TKI Refractory Non-Small-Cell Lung Cancer |
| title_short | Chromosomal Instability Is Associated with cGAS–STING Activation in EGFR-TKI Refractory Non-Small-Cell Lung Cancer |
| title_sort | chromosomal instability is associated with cgas sting activation in egfr tki refractory non small cell lung cancer |
| topic | EGFR-mutated non-small-cell lung cancer epidermal growth factor receptor tyrosine kinase inhibitors chromosomal instability |
| url | https://www.mdpi.com/2073-4409/14/6/447 |
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