2. Academic Validation
  3. The EGFR C797S Mutation Confers Resistance to a Novel EGFR Inhibitor CLN-081 to EGFR Exon 20 Insertion Mutations

The EGFR C797S Mutation Confers Resistance to a Novel EGFR Inhibitor CLN-081 to EGFR Exon 20 Insertion Mutations

  • JTO Clin Res Rep. 2023 Jan 24;4(3):100462. doi: 10.1016/j.jtocrr.2023.100462.
Yosuke Kagawa 1 2 3,  Takuma Hayashida 2 4,  Jie Liu 2,  Shunta Mori 1,  Hiroki Izumi 1,  Shogo Kumagai 5,  Hibiki Udagawa 1 2,  Noboru Hattori 3,  Koichi Goto 1,  Susumu S Kobayashi 2 4 6
Affiliations

Affiliations

  • 1 Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
  • 2 Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
  • 3 Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
  • 4 Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
  • 5 Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
  • 6 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
PMID: 36915628 DOI: 10.1016/j.jtocrr.2023.100462
Abstract

Introduction: EGFR exon 20 insertion mutations account for 5% to 10% of EGFR-mutated NSCLC. CLN-081 (formerly known as TAS6417), a novel covalent EGFR tyrosine kinase inhibitor, exhibits pan-mutation selective efficacy, including exon 20 insertions, in the clinical setting. Nevertheless, 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 complementary DNA to Sequencing to identify acquired mutations. We then evaluated effects of small molecules on engineered Ba/F3 cells on the basis of 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 tyrosine kinase inhibitors 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 suggest a potential small molecule to overcome CLN-081 resistance, which may benefit patients with lung Cancer with EGFR exon 20 insertions.

Keywords

C797S; CLN-081; EGFR; Non–small cell lung cancer; Resistant mechanism.

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