Advertisement

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
    Search for articles by this author
  • 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
    Search for articles by this author
  • Jie Liu
    Affiliations
    Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan
    Search for articles by this author
  • Shunta Mori
    Affiliations
    Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
    Search for articles by this author
  • Hiroki Izumi
    Affiliations
    Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
    Search for articles by this author
  • Shogo Kumagai
    Affiliations
    Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan
    Search for articles by this author
  • 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
    Search for articles by this author
  • 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
    Search for articles by this author
  • Koichi Goto
    Affiliations
    Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
    Search for articles by this author
  • 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
    Search for articles by this author
Open AccessPublished:January 24, 2023DOI:https://doi.org/10.1016/j.jtocrr.2023.100462
      This paper is only available as a PDF. To read, Please Download here.

      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