TAS6417/CLN-081 Is a Pan-Mutation–Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations
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 (wild-type 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 01, 2019
- Source ID
- 10.1158/1541-7786.mcr-19-0419
Entities
People
- Akihiro Hashimoto
- Akihiro Ohashi
- Daniel B Costa
- Hibiki Udagawa
- Hiroyuki Yasuda
- Kaoru Funabashi
- Kazutaka Miyadera
- Koichi Goto
- Miki Terasaka
- Mikiko Shibuya
- Naomi Abe
- Rumi Fujioka
- Ryoto Fujita
- Shinichi Hasako
- Susumu S Kobayashi
- Tomonori Haruma
- Toshiharu Komori
- Yumi Hakozaki
Organizations
- Harvard Medical School
- Japan Society for the Promotion of Science
- Keio University
- National Cancer Center
- National Cancer Center Hospital East
- National Institutes of Health
- United States Department of Defense