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<p>Although EGFR tyrosine kinase inhibitors (EGFR-TKIs) are effective for <i>EGFR</i>-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 <i>EGFR</i>-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 <i>CDKN2A/B</i> loss and are sensitive to CDK4/6 inhibitors. Our <i>EGFR</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月11日

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  • 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

摘要

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.