論文 - 詳細
| RRC ID | 76706 |
|---|---|
| 著者 | Marrocco I, Giri S, Simoni-Nieves A, Gupta N, Rudnitsky A, Haga Y, Romaniello D, Sekar A, Zerbib M, Oren R, Lindzen M, Fard D, Tsutsumi Y, Lauriola M, Tamagnone L, Yarden Y. |
| タイトル | L858R emerges as a potential biomarker predicting response of lung cancer models to anti-EGFR antibodies: Comparison of osimertinib vs. cetuximab. |
| ジャーナル | Cell Rep Med |
| Abstract |
EGFR-specific tyrosine kinase inhibitors (TKIs), especially osimertinib, have changed lung cancer therapy, but secondary mutations confer drug resistance. Because other EGFR mutations promote dimerization-independent active conformations but L858R strictly depends on receptor dimerization, we herein evaluate the therapeutic potential of dimerization-inhibitory monoclonal antibodies (mAbs), including cetuximab. This mAb reduces viability of cells expressing L858R-EGFR and blocks the FOXM1-aurora survival pathway, but other mutants show no responses. Unlike TKI-treated patient-derived xenografts, which relapse post osimertinib treatment, cetuximab completely prevents relapses of L858R+ tumors. We report that osimertinib's inferiority associates with induction of mutagenic reactive oxygen species, whereas cetuximab's superiority is due to downregulation of adaptive survival pathways (e.g., HER2) and avoidance of mutation-prone mechanisms that engage AXL, RAD18, and the proliferating cell nuclear antigen. These results identify L858R as a predictive biomarker, which may pave the way for relapse-free mAb monotherapy relevant to a large fraction of patients with lung cancer. |
| ページ | 101142 |
| 公開日 | 2023-8-3 |
| DOI | 10.1016/j.xcrm.2023.101142 |
| PII | S2666-3791(23)00295-1 |
| PMID | 37557179 |
| PMC | PMC10439256 |
| MeSH | Antibodies, Monoclonal / therapeutic use Biomarkers Cetuximab / pharmacology Cetuximab / therapeutic use DNA-Binding Proteins ErbB Receptors* / genetics Humans Lung Neoplasms* / drug therapy Lung Neoplasms* / genetics Lung Neoplasms* / pathology Neoplasm Recurrence, Local / drug therapy Protein Kinase Inhibitors / pharmacology Ubiquitin-Protein Ligases |
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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 | 29 |
| 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 | II-18(RCB2093) |
| 遺伝子材料 | tFucci(CA)2/pCSII-EF (RDB15446) |