2019年11月
TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations
MOLECULAR CANCER RESEARCH
- 巻
- 17
- 号
- 11
- 開始ページ
- 2233
- 終了ページ
- 2243
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1158/1541-7786.MCR-19-0419
- 出版者・発行元
- AMER ASSOC CANCER RESEARCH
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.
- リンク情報
-
- DOI
- https://doi.org/10.1158/1541-7786.MCR-19-0419
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/31467113
- PubMed Central
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872223
- Web of Science
- https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000494368800008&DestApp=WOS_CPL
- ID情報
-
- DOI : 10.1158/1541-7786.MCR-19-0419
- ISSN : 1541-7786
- eISSN : 1557-3125
- PubMed ID : 31467113
- PubMed Central 記事ID : PMC6872223
- Web of Science ID : WOS:000494368800008