論文 - 詳細
| RRC ID | 63055 |
|---|---|
| 著者 | Wang R, Yamada T, Kita K, Taniguchi H, Arai S, Fukuda K, Terashima M, Ishimura A, Nishiyama A, Tanimoto A, Takeuchi S, Ohtsubo K, Yamashita K, Yamano T, Yoshimura A, Takayama K, Kaira K, Taniguchi Y, Atagi S, Uehara H, Hanayama R, Matsumoto I, Han X, Matsumoto K, Wang W, Suzuki T, Yano S. |
| タイトル | Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer. |
| ジャーナル | Nat Commun |
| Abstract |
Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC. |
| 巻・号 | 11(1) |
| ページ | 4607 |
| 公開日 | 2020-9-14 |
| DOI | 10.1038/s41467-020-18442-4 |
| PII | 10.1038/s41467-020-18442-4 |
| PMID | 32929081 |
| PMC | PMC7490421 |
| MeSH | Acrylamides / pharmacology Acrylamides / therapeutic use* Aged, 80 and over Aniline Compounds / pharmacology Aniline Compounds / therapeutic use* Animals Axl Receptor Tyrosine Kinase Carcinoma, Non-Small-Cell Lung / drug therapy Carcinoma, Non-Small-Cell Lung / genetics Carcinoma, Non-Small-Cell Lung / pathology Cell Line, Tumor Cell Survival / drug effects ErbB Receptors / genetics Gene Expression Regulation, Neoplastic / drug effects Hepatocyte Nuclear Factor 3-alpha / metabolism Humans Imidazoles / pharmacology Lung Neoplasms / drug therapy* Lung Neoplasms / genetics* Lung Neoplasms / pathology Male Mice Models, Biological Mutation / genetics* Phosphorylation / drug effects Proto-Oncogene Proteins / metabolism* Pyrazines / pharmacology RNA, Messenger / genetics RNA, Messenger / metabolism Receptor Protein-Tyrosine Kinases / metabolism* Receptor, IGF Type 1 / antagonists & inhibitors* Receptor, IGF Type 1 / genetics Receptor, IGF Type 1 / metabolism Up-Regulation / drug effects |
| IF | 12.121 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | News |
| 各媒体での言及数の合計 | 31 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | PC-9(RCB4455) |