論文 - 詳細
| RRC ID | 66852 |
|---|---|
| 著者 | Okura N, Nishioka N, Yamada T, Taniguchi H, Tanimura K, Katayama Y, Yoshimura A, Watanabe S, Kikuchi T, Shiotsu S, Kitazaki T, Nishiyama A, Iwasaku M, Kaneko Y, Uchino J, Uehara H, Horinaka M, Sakai T, Tanaka K, Kozaki R, Yano S, Takayama K. |
| タイトル | ONO-7475, a Novel AXL Inhibitor, Suppresses the Adaptive Resistance to Initial EGFR-TKI Treatment in EGFR-Mutated Non-Small Cell Lung Cancer. |
| ジャーナル | Clin Cancer Res |
| Abstract |
PURPOSE:Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating EGFR-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we investigated the best therapeutic strategy to combat AXL-induced tolerance to EGFR-TKIs using the novel AXL inhibitor ONO-7475. EXPERIMENTAL DESIGN:We examined the efficacy of ONO-7475 in combination with EGFR-TKIs in EGFR-mutated NSCLC cells using in vitro and in vivo experiments. We investigated the correlation between AXL expression in tumors and clinical outcomes with osimertinib for EGFR-mutated NSCLC patients with acquired resistance to initial EGFR-TKIs. RESULTS:ONO-7475 sensitized AXL-overexpressing EGFR-mutant NSCLC cells to the EGFR-TKIs osimertinib and dacomitinib. In addition, ONO-7475 suppressed the emergence and maintenance of EGFR-TKI-tolerant cells. In the cell line-derived xenograft models of AXL-overexpressing EGFR-mutated lung cancer treated with osimertinib, initial combination therapy of ONO-7475 and osimertinib markedly regressed tumors and delayed tumor regrowth compared with osimertinib alone or the combination after acquired resistance to osimertinib. AXL expression in EGFR-TKI refractory tumors did not correlate with the sensitivity of osimertinib. CONCLUSIONS:These results demonstrate that ONO-7475 suppresses the emergence and maintenance of tolerant cells to the initial EGFR-TKIs, osimertinib or dacomitinib, in AXL-overexpressing EGFR-mutated NSCLC cells, suggesting that ONO-7475 and osimertinib is a highly potent combination for initial treatment. |
| 巻・号 | 26(9) |
| ページ | 2244-2256 |
| 公開日 | 2020-5-1 |
| DOI | 10.1158/1078-0432.CCR-19-2321 |
| PII | 1078-0432.CCR-19-2321 |
| PMID | 31953310 |
| MeSH | Acrylamides / pharmacology* Aniline Compounds / pharmacology* Animals Axl Receptor Tyrosine Kinase Biomarkers, Tumor / metabolism Carcinoma, Non-Small-Cell Lung / drug therapy* Carcinoma, Non-Small-Cell Lung / genetics Carcinoma, Non-Small-Cell Lung / metabolism Carcinoma, Non-Small-Cell Lung / pathology Cell Line, Tumor Drug Resistance, Neoplasm ErbB Receptors / antagonists & inhibitors ErbB Receptors / genetics ErbB Receptors / metabolism Humans Lung Neoplasms / drug therapy* Lung Neoplasms / genetics Lung Neoplasms / metabolism Lung Neoplasms / pathology Male Mice Mice, SCID Mutation* Protein Kinase Inhibitors / pharmacology* Proto-Oncogene Proteins / antagonists & inhibitors* Proto-Oncogene Proteins / metabolism Quinolines / pharmacology* Receptor Protein-Tyrosine Kinases / antagonists & inhibitors* Receptor Protein-Tyrosine Kinases / metabolism Xenograft Model Antitumor Assays |
| IF | 10.107 |
| リソース情報 | |
| ヒト・動物細胞 | PC-9(RCB4455) |