TAS6417/CLN-081 is a pan-mutation-selective EGFR tyrosine kinase inhibitor with a broad spectrum of preclinical activity against clinically relevant EGFR mutations

Hibiki Udagawa, Shinichi Hasako, Akihiro Ohashi, Rumi Fujioka, Yumi Hakozaki, Mikiko Shibuya, Naomi Abe, Toshiharu Komori, Tomonori Haruma, Miki Terasaka, Ryoto Fujita, Akihiro Hashimoto, Kaoru Funabashi, Hiroyuki Yasuda, Kazutaka Miyadera, Koichi Goto, Daniel B. Costa, Susumu S. Kobayashi

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Despite the worldwide approval of three generations of EGFR tyrosine kinase inhibitors (TKI) for advanced non- small cell lung cancers with EGFR mutations, no TKI with a broad spectrum of activity against all clinically relevant mutations is currently available. In this study, we sought to evaluate a covalent mutation-specific EGFR TKI, TAS6417 (also named CLN-081), with the broadest level of activity against EGFR mutations with a prevalence of ≥1%. Lung cancer and genetically engineered cell lines, as well as murine xenograft models were used to evaluate the efficacy of TAS6417 and other approved/in-development EGFR TKIs (erlotinib, afatinib, osimertinib, and poziotinib). We demonstrate that TAS6417 is a robust inhibitor against the most common EGFR mutations (exon 19 deletions and L858R) and the most potent against cells harboring EGFR-T790M (first/second-generation TKI resistance mutation). In addition, TAS6417 has activity in cells driven by less common EGFR-G719X, L861Q, and S768I mutations. For recalcitrant EGFR exon 20 insertion mutations, selectivity indexes (wildtype EGFR/mutant EGFR ratio of inhibition) favored TAS6417 in comparison with poziotinib and osimertinib, indicating a wider therapeutic window. Taken together, we demonstrate that TAS6417 is a potent EGFR TKI with a broad spectrum of activity and a wider therapeutic window than most approved/in-development generations of EGFR inhibitors.

Original languageEnglish
Pages (from-to)2233-2243
Number of pages11
JournalMolecular Cancer Research
Volume17
Issue number11
DOIs
Publication statusPublished - 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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