Basal-shift transformation leads to EGFR therapy-resistance in human lung adenocarcinoma

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 () and Toshiro Sato ()
Additional contact information
Taro Shinozaki: School of Medicine
Kazuhiro Togasaki: Keio University School of Medicine
Junko Hamamoto: School of Medicine
Akifumi Mitsuishi: School of Medicine
Takahiro Fukushima: School of Medicine
Kai Sugihara: School of Medicine
Toshiki Ebisudani: School of Medicine
Masahiko Okada: School of Medicine
Ayaka Saito: School of Medicine
Lisa Shigematsu: School of Medicine
Hatsuyo Takaoka: School of Medicine
Fumimaro Ito: School of Medicine
Keiko Ohgino: School of Medicine
Kota Ishioka: School of Medicine
Kageaki Watanabe: Komagome Hospital
Tsunekazu Hishima: Komagome Hospital
Yutaka Kurebayashi: Keio University School of Medicine
Katsura Emoto: Keio University School of Medicine
Hideki Terai: School of Medicine
Shinnosuke Ikemura: School of Medicine
Ichiro Kawada: School of Medicine
Keisuke Asakura: Keio University School of Medicine
Tomoyuki Hishida: Keio University School of Medicine
Hisao Asamura: Keio University School of Medicine
Yuki Ohta: Keio University School of Medicine
Sirirat Takahashi: Keio University School of Medicine
Mayumi Oda: Keio University School of Medicine
Megumu Saito: Keio University School of Medicine
Mami Matano: Keio University School of Medicine
Kenzo Soejima: School of Medicine
Masayuki Fujii: Keio University School of Medicine
Koichi Fukunaga: School of Medicine
Hiroyuki Yasuda: School of Medicine
Toshiro Sato: Keio University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59623-3

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