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 K. Saito, Mami Matano, Kenzo Soejima, Masayuki Fujii, Koichi Fukunaga, Hiroyuki Yasuda, Toshiro Sato
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. Resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) is prevalent. Here the authors establish a biobank of patient-derived EGFR-mutant lung cancer organoids and identify a subgroup of EGFR-TKI-resistant lung adenocarcinoma organoids, which exhibit a basal-shift phenotype and vulnerability to CDK4/6 inhibitors.