論文 - 詳細
| RRC ID | 76974 |
|---|---|
| 著者 | Nishino M, Suda K, Koga T, Ohara S, Fujino T, Soh J, Tirunagaru V, Vellanki A, Doebele RC, Mitsudomi T. |
| タイトル | Activity of tarloxotinib-E in cells with EGFR exon-20 insertion mutations and mechanisms of acquired resistance. |
| ジャーナル | Thorac Cancer |
| Abstract |
BACKGROUND:Approximately 10% of non-small cell lung cancers (NSCLCs) that harbor epidermal growth factor receptor (EGFR) gene mutations have in-frame insertions in exon 20 of the EGFR gene. These tumors do not usually respond to currently available EGFR-tyrosine kinase inhibitors (TKIs). Tarloxotinib is a novel hypoxia-activated prodrug that releases a potent, irreversible pan-ERBB TKI (tarloxotinib-E) under solid tumor hypoxia. METHODS:We examined the efficacy of tarloxotinib-E against several types of Ba/F3 cells with introduced EGFR exon 20 mutations (EGFR A763insFQEA, V769insASV, D770insSVD, H773insH and H773insNPH mutations). We assayed growth inhibition for tarloxotinib (prodrug), tarloxotinib-E (active form), poziotinib, afatinib, and osimertinib in Ba/F3 cells with each EGFR exon 20 mutation. We also explored acquired resistance mechanisms to tarloxotinib-E by establishing cells with resistance to tarloxotinib-E via chronic drug exposure after N-ethyl-N-nitrosourea mutagenesis treatment. RESULTS:Among all tested Ba/F3 cell lines, IC50 was ≥72.1 times higher for tarloxotinib than for tarloxotinib-E, which implies a wide therapeutic window with this prodrug strategy. Tarloxotinib-E was efficacious against all tested Ba/F3 cells except for H773insH, which was less sensitive to all tested EGFR-TKIs. As acquired resistance mechanisms to tarloxotinib-E, we identified either T790M or C797S secondary mutations, depending on the original EGFR exon 20 mutation. CONCLUSIONS:These findings indicate that tarloxotinib-E could be effective for NSCLC with EGFR exon 20 mutations. Our results also show that T790M or C797S mutations can confer acquired resistance to tarloxotinib-E; and suggest that resistance mechanisms are influenced by the baseline EGFR exon 20 mutations. |
| 巻・号 | 12(10) |
| ページ | 1511-1516 |
| 公開日 | 2021-5-1 |
| DOI | 10.1111/1759-7714.13931 |
| PMID | 33710795 |
| PMC | PMC8107039 |
| MeSH | Drug Resistance, Neoplasm / immunology* ErbB Receptors / metabolism Exons / genetics* Humans Molecular Targeted Therapy / methods* Mutagenesis, Insertional Mutation |
| IF | 2.524 |
| リソース情報 | |
| ヒト・動物細胞 | Ba/F3 |