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Research Article|Articles in Press, 100462

The EGFR C797S mutation confers resistance to a novel EGFR inhibitor CLN-081 to EGFR exon 20 insertion mutations

  • Yosuke Kagawa
    Affiliations
    Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan

    Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan

    Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
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  • Takuma Hayashida
    Affiliations
    Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan

    Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-8561, Japan
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  • Jie Liu
    Affiliations
    Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan
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  • Shunta Mori
    Affiliations
    Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
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  • Hiroki Izumi
    Affiliations
    Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
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  • Shogo Kumagai
    Affiliations
    Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan
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  • Hibiki Udagawa
    Affiliations
    Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan

    Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan
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  • Noboru Hattori
    Affiliations
    Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
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  • Koichi Goto
    Affiliations
    Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
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  • Susumu S. Kobayashi
    Correspondence
    Correspondence to: Susumu S. Kobayashi, M.D., Ph.D.: Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, 277-8577, Japan.
    Affiliations
    Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan

    Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-8561, Japan

    Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Open AccessPublished:January 24, 2023DOI:https://doi.org/10.1016/j.jtocrr.2023.100462
The EGFR C797S mutation confers resistance to a novel EGFR inhibitor CLN-081 to EGFR exon 20 insertion mutations
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      Abstract

      Introduction

      Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for 5-10% of EGFR-mutated non-small cell lung cancer. CLN-081 (formerly known as TAS6417), a novel covalent EGFR-tyrosine kinase inhibitor (TKI), exhibits pan-mutation selective efficacy, including exon 20 insertions, in the clinical setting. However, some patients may not respond to CLN-081 and resistance to CLN-081 may emerge over time in others.

      Methods

      We exposed Ba/F3 cells transduced with EGFR exon 20 insertions (Y764_V765 insHH or A767_S768insSVD) to increasing concentrations of CLN-081 to generate resistant cells and then subjected their cDNA to sequencing to identify acquired mutations. We then evaluated effects of small molecules on engineered Ba/F3 cells based on proliferation assays, western blotting, and xenograft models.

      Results

      All CLN-081 resistant clones harbored the EGFR C797S mutation. Ba/F3 cells with C797S (Ba/F3-C797S) were resistant to EGFR TKIs targeting EGFR exon 20 insertion mutations, including CLN-081. Pimitespib, a selective heat shock protein 90 inhibitor, induced apoptosis in Ba/F3-C797S cells in vitro and inhibited growth of Ba/F3-C797S tumors in vivo. Ba/F3 cells with A763_Y764insFQEA-C797S remained sensitive to erlotinib.

      Conclusions

      We conclude that the EGFR C797S mutation confers resistance to CLN-081. Our preclinical data suggests a potential small molecule to overcome CLN-081 resistance, which may benefit lung cancer patients with EGFR exon 20 insertions.

      Keywords

      Article info

      Publication history

      Accepted: January 11, 2023
      Received in revised form: January 5, 2023
      Received: November 30, 2022

      Publication stage

      In Press Journal Pre-Proof

      Footnotes

      Funding information

      This work was supported by TAIHO Pharmaceutical Co. Ltd (C2020-097), the Princess Takamatsu Cancer Research Fund 18-250 (S.S.K), JSPS KAKENHI Grant Number JP20K17215 (H.I.), 16K21746 (S.S.K.), JPJSBP120207408 (S.S.K.) and 22H03084 (S.S.K.), and the National Cancer Center Research and Development Fund 31-A-6 (S.S.K).

      Declaration of interests

      Y.K., T.H., J.L., and S.M report no conflicts of interest. H.I. reports grants from Amgen, Ono, Takeda, and Eisai and personal fees from Ono, Chugai, AstraZeneca, Merck, and Takeda. S.K. reports personal fees from MSD and Chugai. H.U. reports grants from Takeda and Boehringer Ingelheim. N.H. reports personal fees from Boehringer Ingelheim and AstraZeneca. K.G. reports grants from Merck, Takeda Pharmaceutical, Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Janssen, Kyowa Kirin, Lilly, Medical & Biological Laboratories, MSD, Novartis, Ono, Pfizer, Sumitomo Dainippon, Bayer, Haihe Biopharma, Ignyta, Kissei, Life Technologies Japan, Loxo Oncology, Merus, Pfizer, Spectrum Pharmaceuticals, Sysmex Corporation, Turning Point Therapeutics, and Taiho and grants and personal fees from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Blueprint Medicines, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Janssen, Merck, MS, Novartis, Ono, Taiho, and Takeda and personal fees from Amoy Diagnostics, Bayer, Guardant Health, Thermo Fisher Scientific, Medpace, and Otsuka. SSK reports research support from Boehringer Ingelheim, MiRXES, Johnson&Johnson, and Taiho Therapeutics, as well as personal fees (honoraria) from AstraZeneca, Boehringer Ingelheim, Bristol Meyers Squibb, Chugai Pharmaceutical, and Takeda Pharmaceuticals.

      CRediT Authorship Contribution Statement

      Yosuke Kagawa: Conceptualization, Investigation, Methodology, Formal analysis, Writing – original draft, and Visualization.

      Takuma Hayashida, Jie Liu, Shunta Mori, Shogo Kumagai: Investigation.

      Hibiki Udagawa: Methodology and Conceptualization.

      Noboru Hattori and Koichi Goto: Writing – review & editing.

      Susumu S. Kobayashi: Conceptualization, Investigation, Methodology, Formal analysis, Writing – original draft, Visualization, Supervision, Funding acquisition, and Project administration.

      Identification

      DOI: https://doi.org/10.1016/j.jtocrr.2023.100462

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      © 2023 Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer.

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