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15357163mct171206-sup-193440_2_supp_4676769_p6tbmm.pdf (28.72 kB)

Supplementary Methods from TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion Mutations

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posted on 2023-04-03, 15:02 authored by Shinichi Hasako, Miki Terasaka, Naomi Abe, Takao Uno, Hirokazu Ohsawa, Akihiro Hashimoto, Ryoto Fujita, Kenji Tanaka, Takashige Okayama, Renu Wadhwa, Kazutaka Miyadera, Yoshimi Aoyagi, Kazuhiko Yonekura, Kenichi Matsuo

Methods for in vitro kinase assay, genome sequence, and immunoblotting analysis

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ARTICLE ABSTRACT

Activating mutations in the EGFR gene are important targets in cancer therapy because they are key drivers of non–small cell lung cancer (NSCLC). Although almost all common EGFR mutations, such as exon 19 deletions and the L858R point mutation in exon 21, are sensitive to EGFR-tyrosine kinase inhibitor (TKI) therapies, NSCLC driven by EGFR exon 20 insertion mutations is associated with poor clinical outcomes due to dose-limiting toxicity, demonstrating the need for a novel therapy. TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations. Mol Cancer Ther; 17(8); 1648–58. ©2018 AACR.

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