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

Yosuke Kagawa; Takuma Hayashida; Jie Liu; Shunta Mori; Hiroki Izumi; Shogo Kumagai; Hibiki Udagawa; Noboru Hattori; Koichi Goto; Susumu S Kobayashi

doi: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

JTO Clin Res Rep. 2023 Jan 24;4(3):100462. doi: 10.1016/j.jtocrr.2023.100462. eCollection 2023 Mar.

Authors

Yosuke Kagawa^{1

2

3}, Takuma Hayashida^{2

4}, Jie Liu², Shunta Mori¹, Hiroki Izumi¹, Shogo Kumagai⁵, Hibiki Udagawa^{1

2}, Noboru Hattori³, Koichi Goto¹, Susumu S Kobayashi^{2

4

6}

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.

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.