Basal-shift transformation leads to EGFR therapy-resistance in human lung adenocarcinoma
Abstract Although EGFR tyrosine kinase inhibitors (EGFR-TKIs) are effective for EGFR-mutant lung adenocarcinoma (LUAD), resistance inevitably develops through diverse mechanisms, including secondary genetic mutations, amplifications and as-yet undefined processes. To comprehensively unravel the mech...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59623-3 |
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| author | Taro Shinozaki Kazuhiro Togasaki Junko Hamamoto Akifumi Mitsuishi Takahiro Fukushima Kai Sugihara Toshiki Ebisudani Masahiko Okada Ayaka Saito Lisa Shigematsu Hatsuyo Takaoka Fumimaro Ito Keiko Ohgino Kota Ishioka Kageaki Watanabe Tsunekazu Hishima Yutaka Kurebayashi Katsura Emoto Hideki Terai Shinnosuke Ikemura Ichiro Kawada Keisuke Asakura Tomoyuki Hishida Hisao Asamura Yuki Ohta Sirirat Takahashi Mayumi Oda Megumu Saito Mami Matano Kenzo Soejima Masayuki Fujii Koichi Fukunaga Hiroyuki Yasuda Toshiro Sato |
| author_facet | Taro Shinozaki Kazuhiro Togasaki Junko Hamamoto Akifumi Mitsuishi Takahiro Fukushima Kai Sugihara Toshiki Ebisudani Masahiko Okada Ayaka Saito Lisa Shigematsu Hatsuyo Takaoka Fumimaro Ito Keiko Ohgino Kota Ishioka Kageaki Watanabe Tsunekazu Hishima Yutaka Kurebayashi Katsura Emoto Hideki Terai Shinnosuke Ikemura Ichiro Kawada Keisuke Asakura Tomoyuki Hishida Hisao Asamura Yuki Ohta Sirirat Takahashi Mayumi Oda Megumu Saito Mami Matano Kenzo Soejima Masayuki Fujii Koichi Fukunaga Hiroyuki Yasuda Toshiro Sato |
| author_sort | Taro Shinozaki |
| collection | DOAJ |
| description | Abstract Although EGFR tyrosine kinase inhibitors (EGFR-TKIs) are effective for EGFR-mutant lung adenocarcinoma (LUAD), resistance inevitably develops through diverse mechanisms, including secondary genetic mutations, amplifications and as-yet undefined processes. To comprehensively unravel the mechanisms of EGFR-TKI resistance, we establish a biobank of patient-derived EGFR-mutant lung cancer organoids, encompassing cases previously treated with EGFR-TKIs. Through comprehensive molecular profiling including single-cell analysis, here we identify a subgroup of EGFR-TKI-resistant LUAD organoids that lacks known resistance-related genetic lesions and instead exhibits a basal-shift phenotype characterized by the hybrid expression of LUAD- and squamous cell carcinoma-related genes. Prospective gene engineering demonstrates that NKX2-1 knockout induces the basal-shift transformation along with EGFR-target therapy resistance. Basal-shift LUADs frequently harbor CDKN2A/B loss and are sensitive to CDK4/6 inhibitors. Our EGFR-mutant lung cancer organoid library not only offers a valuable resource for lung cancer research but also provides insights into molecular underpinnings of EGFR-TKI resistance, facilitating the development of therapeutic strategies. |
| format | Article |
| id | doaj-art-b4be12c8f7bf43dca94b4167e3d2c5f9 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b4be12c8f7bf43dca94b4167e3d2c5f92025-08-20T03:10:30ZengNature PortfolioNature Communications2041-17232025-05-0116111510.1038/s41467-025-59623-3Basal-shift transformation leads to EGFR therapy-resistance in human lung adenocarcinomaTaro Shinozaki0Kazuhiro Togasaki1Junko Hamamoto2Akifumi Mitsuishi3Takahiro Fukushima4Kai Sugihara5Toshiki Ebisudani6Masahiko Okada7Ayaka Saito8Lisa Shigematsu9Hatsuyo Takaoka10Fumimaro Ito11Keiko Ohgino12Kota Ishioka13Kageaki Watanabe14Tsunekazu Hishima15Yutaka Kurebayashi16Katsura Emoto17Hideki Terai18Shinnosuke Ikemura19Ichiro Kawada20Keisuke Asakura21Tomoyuki Hishida22Hisao Asamura23Yuki Ohta24Sirirat Takahashi25Mayumi Oda26Megumu Saito27Mami Matano28Kenzo Soejima29Masayuki Fujii30Koichi Fukunaga31Hiroyuki Yasuda32Toshiro Sato33Division of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDepartment of Integrative Medicine and Biochemistry, Keio University School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDepartment of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome HospitalDepartment of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome HospitalDepartment of Pathology, Keio University School of MedicineDepartment of Pathology, Keio University School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDivision of Thoracic Surgery, Keio University School of MedicineDivision of Thoracic Surgery, Keio University School of MedicineDivision of Thoracic Surgery, Keio University School of MedicineDepartment of Integrative Medicine and Biochemistry, Keio University School of MedicineDepartment of Integrative Medicine and Biochemistry, Keio University School of MedicineDepartment of Integrative Medicine and Biochemistry, Keio University School of MedicineDepartment of Organoid Medicine, Keio University School of MedicineDepartment of Integrative Medicine and Biochemistry, Keio University School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDepartment of Integrative Medicine and Biochemistry, Keio University School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDivision of Pulmonary Medicine, Department of Medicine, Keio University, School of MedicineDepartment of Integrative Medicine and Biochemistry, Keio University School of MedicineAbstract Although EGFR tyrosine kinase inhibitors (EGFR-TKIs) are effective for EGFR-mutant lung adenocarcinoma (LUAD), resistance inevitably develops through diverse mechanisms, including secondary genetic mutations, amplifications and as-yet undefined processes. To comprehensively unravel the mechanisms of EGFR-TKI resistance, we establish a biobank of patient-derived EGFR-mutant lung cancer organoids, encompassing cases previously treated with EGFR-TKIs. Through comprehensive molecular profiling including single-cell analysis, here we identify a subgroup of EGFR-TKI-resistant LUAD organoids that lacks known resistance-related genetic lesions and instead exhibits a basal-shift phenotype characterized by the hybrid expression of LUAD- and squamous cell carcinoma-related genes. Prospective gene engineering demonstrates that NKX2-1 knockout induces the basal-shift transformation along with EGFR-target therapy resistance. Basal-shift LUADs frequently harbor CDKN2A/B loss and are sensitive to CDK4/6 inhibitors. Our EGFR-mutant lung cancer organoid library not only offers a valuable resource for lung cancer research but also provides insights into molecular underpinnings of EGFR-TKI resistance, facilitating the development of therapeutic strategies.https://doi.org/10.1038/s41467-025-59623-3 |
| spellingShingle | Taro Shinozaki Kazuhiro Togasaki Junko Hamamoto Akifumi Mitsuishi Takahiro Fukushima Kai Sugihara Toshiki Ebisudani Masahiko Okada Ayaka Saito Lisa Shigematsu Hatsuyo Takaoka Fumimaro Ito Keiko Ohgino Kota Ishioka Kageaki Watanabe Tsunekazu Hishima Yutaka Kurebayashi Katsura Emoto Hideki Terai Shinnosuke Ikemura Ichiro Kawada Keisuke Asakura Tomoyuki Hishida Hisao Asamura Yuki Ohta Sirirat Takahashi Mayumi Oda Megumu Saito Mami Matano Kenzo Soejima Masayuki Fujii Koichi Fukunaga Hiroyuki Yasuda Toshiro Sato Basal-shift transformation leads to EGFR therapy-resistance in human lung adenocarcinoma Nature Communications |
| title | Basal-shift transformation leads to EGFR therapy-resistance in human lung adenocarcinoma |
| title_full | Basal-shift transformation leads to EGFR therapy-resistance in human lung adenocarcinoma |
| title_fullStr | Basal-shift transformation leads to EGFR therapy-resistance in human lung adenocarcinoma |
| title_full_unstemmed | Basal-shift transformation leads to EGFR therapy-resistance in human lung adenocarcinoma |
| title_short | Basal-shift transformation leads to EGFR therapy-resistance in human lung adenocarcinoma |
| title_sort | basal shift transformation leads to egfr therapy resistance in human lung adenocarcinoma |
| url | https://doi.org/10.1038/s41467-025-59623-3 |
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