論文 - 詳細
| RRC ID | 68842 |
|---|---|
| 著者 | Fukuda K, Otani S, Takeuchi S, Arai S, Nanjo S, Tanimoto A, Nishiyama A, Naoki K, Yano S. |
| タイトル | Trametinib overcomes KRAS-G12V-induced osimertinib resistance in a leptomeningeal carcinomatosis model of EGFR-mutant lung cancer. |
| ジャーナル | Cancer Sci |
| Abstract |
Leptomeningeal carcinomatosis (LMC) occurs frequently in non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and is associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, the mechanism by which LMC acquires resistance to osimertinib, a third-generation EGFR-TKI, is unclear. In this study, we elucidated the resistance mechanism and searched for a novel therapeutic strategy. We induced osimertinib resistance in a mouse model of LMC using an EGFR-mutant NSCLC cell line (PC9) via continuous oral osimertinib treatment and administration of established resistant cells and examined the resistance mechanism using next-generation sequencing. We detected the Kirsten rat sarcoma (KRAS)-G12V mutation in resistant cells, which retained the EGFR exon 19 deletion. Experiments involving KRAS knockdown in resistant cells and KRAS-G12V overexpression in parental cells revealed the involvement of KRAS-G12V in osimertinib resistance. Cotreatment with trametinib (a MEK inhibitor) and osimertinib resensitized the cells to osimertinib. Furthermore, in the mouse model of LMC with resistant cells, combined osimertinib and trametinib treatment successfully controlled LMC progression. These findings suggest a potential novel therapy against KRAS-G12V-harboring osimertinib-resistant LMC in EGFR-mutant NSCLC. |
| 巻・号 | 112(9) |
| ページ | 3784-3795 |
| 公開日 | 2021-9-1 |
| DOI | 10.1111/cas.15035 |
| PMID | 34145930 |
| PMC | PMC8409422 |
| MeSH | Acrylamides / administration & dosage* Aniline Compounds / administration & dosage* Animals Antineoplastic Agents / administration & dosage* 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 Cell Survival / drug effects Cell Survival / genetics Codon / genetics* Drug Resistance, Neoplasm / drug effects* Drug Resistance, Neoplasm / genetics 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 Meningeal Carcinomatosis / drug therapy* Meningeal Carcinomatosis / genetics Meningeal Carcinomatosis / metabolism Mice Mice, SCID Mutation* Protein Kinase Inhibitors / administration & dosage* Proto-Oncogene Proteins p21(ras) / genetics* Proto-Oncogene Proteins p21(ras) / metabolism Pyridones / administration & dosage* Pyridones / pharmacology Pyrimidinones / administration & dosage* Pyrimidinones / pharmacology Transfection Treatment Outcome Xenograft Model Antitumor Assays |
| IF | 4.966 |
| リソース情報 | |
| ヒト・動物細胞 | PC-9(RCB4455) |