IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-59623-3.html
   My bibliography  Save this article

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

Author

Listed:
  • Taro Shinozaki

    (School of Medicine)

  • Kazuhiro Togasaki

    (Keio University School of Medicine
    Keio University School of Medicine
    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
    Keio University 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
    Keio University School of Medicine)

  • Sirirat Takahashi

    (Keio University School of Medicine
    Keio University School of Medicine)

  • Mayumi Oda

    (Keio University School of Medicine
    Keio University School of Medicine)

  • Megumu Saito

    (Keio University School of Medicine
    Osaka Research Center for Drug Discovery)

  • Mami Matano

    (Keio University School of Medicine
    Keio University School of Medicine)

  • Kenzo Soejima

    (School of Medicine)

  • Masayuki Fujii

    (Keio University School of Medicine
    Keio University School of Medicine)

  • Koichi Fukunaga

    (School of Medicine)

  • Hiroyuki Yasuda

    (School of Medicine)

  • Toshiro Sato

    (Keio University School of Medicine
    Keio University School of Medicine)

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.

Suggested Citation

  • Taro Shinozaki & Kazuhiro Togasaki & Junko Hamamoto & Akifumi Mitsuishi & Takahiro Fukushima & Kai Sugihara & Toshiki Ebisudani & Masahiko Okada & Ayaka Saito & Lisa Shigematsu & Hatsuyo Takaoka & Fum, 2025. "Basal-shift transformation leads to EGFR therapy-resistance in human lung adenocarcinoma," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59623-3
    DOI: 10.1038/s41467-025-59623-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-59623-3
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-59623-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Minsuh Kim & Hyemin Mun & Chang Oak Sung & Eun Jeong Cho & Hye-Joon Jeon & Sung-Min Chun & Da Jung Jung & Tae Hoon Shin & Gi Seok Jeong & Dong Kwan Kim & Eun Kyung Choi & Seong-Yun Jeong & Alison M. T, 2019. "Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    2. Juliann Chmielecki & Tony Mok & Yi-Long Wu & Ji-Youn Han & Myung-Ju Ahn & Suresh S. Ramalingam & Thomas John & Isamu Okamoto & James Chih-Hsin Yang & Frances A. Shepherd & Krishna C. Bulusu & Gianluca, 2023. "Analysis of acquired resistance mechanisms to osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer from the AURA3 trial," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    3. Hirokazu Taniguchi & Tadaaki Yamada & Rong Wang & Keiko Tanimura & Yuta Adachi & Akihiro Nishiyama & Azusa Tanimoto & Shinji Takeuchi & Luiz H. Araujo & Mariana Boroni & Akihiro Yoshimura & Shinsuke S, 2019. "AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    4. Jana Fassunke & Fabienne Müller & Marina Keul & Sebastian Michels & Marcel A. Dammert & Anna Schmitt & Dennis Plenker & Jonas Lategahn & Carina Heydt & Johannes Brägelmann & Hannah L. Tumbrink & Yanni, 2018. "Overcoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    5. Rong Wang & Tadaaki Yamada & Kenji Kita & Hirokazu Taniguchi & Sachiko Arai & Koji Fukuda & Minoru Terashima & Akihiko Ishimura & Akihiro Nishiyama & Azusa Tanimoto & Shinji Takeuchi & Koshiro Ohtsubo, 2020. "Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Fan Chen & Aria L. Byrd & Jinpeng Liu & Robert M. Flight & Tanner J. DuCote & Kassandra J. Naughton & Xiulong Song & Abigail R. Edgin & Alexsandr Lukyanchuk & Danielle T. Dixon & Christian M. Gosser &, 2023. "Polycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Sarah Figarol & Célia Delahaye & Rémi Gence & Aurélia Doussine & Juan Pablo Cerapio & Mathylda Brachais & Claudine Tardy & Nicolas Béry & Raghda Asslan & Jacques Colinge & Jean-Philippe Villemin & Ant, 2024. "Farnesyltransferase inhibition overcomes oncogene-addicted non-small cell lung cancer adaptive resistance to targeted therapies," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Julia Ogden & Robert Sellers & Sudhakar Sahoo & Anthony Oojageer & Anshuman Chaturvedi & Caroline Dive & Carlos Lopez-Garcia, 2025. "A human model to deconvolve genotype-phenotype causations in lung squamous cell carcinoma," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    4. Louisa L. Y. Chan & Danielle E. Anderson & Hong Sheng Cheng & Fransiskus Xaverius Ivan & Si Chen & Adrian E. Z. Kang & Randy Foo & Akshamal M. Gamage & Pei Yee Tiew & Mariko Siyue Koh & Ken Cheah Hooi, 2022. "The establishment of COPD organoids to study host-pathogen interaction reveals enhanced viral fitness of SARS-CoV-2 in bronchi," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    5. Kyu Jin Song & Seunghyuk Choi & Kwoneel Kim & Hee Sang Hwang & Eunhyong Chang & Ji Soo Park & Seok Bo Shim & Seunghwan Choi & Yong Jin Heo & Woo Ju An & Dae Yeol Yang & Kyung-Cho Cho & Wonjun Ji & Cha, 2024. "Proteogenomic analysis reveals non-small cell lung cancer subtypes predicting chromosome instability, and tumor microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    6. Ranjan Preet & Md Atiqul Islam & Jiyoung Shim & Ganeshkumar Rajendran & Amrita Mitra & Vikalp Vishwakarma & Caleb Kutz & Sonali Choudhury & Harsh Pathak & Qun Dai & Weijing Sun & Rashna Madan & Cuncon, 2025. "Gut commensal Bifidobacterium-derived extracellular vesicles modulate the therapeutic effects of anti-PD-1 in lung cancer," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    7. Rebecca S. Schneider & Elisa B. Nieves & Bhavay Aggarwal & Annie C. Bowles-Welch & Hazel Y. Stevens & Linda E. Kippner & Scott D. Boden & Kenneth Mautner & Hicham Drissi & Krishnendu Roy & Wilbur A. L, 2025. "On-chip 3D potency assay for prediction of clinical outcomes for cell therapy candidates for osteoarthritis," Nature Communications, Nature, vol. 16(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59623-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.