論文 - 詳細
| RRC ID | 81893 |
|---|---|
| 著者 | Simoni-Nieves A, Lindzen M, Giri S, Gupta N, Chatterjee R, Selvadurai BR, Van Daele M, Love D, Haga Y, Romaniello D, Salame TM, Zerbib M, Oren R, Tsutsumi Y, Lauriola M, Marrocco I, Yarden Y. |
| タイトル | A bispecific antibody targeting EGFR and AXL delays resistance to osimertinib. |
| ジャーナル | Cell Rep Med |
| Abstract |
Activating EGFR (epidermal growth factor receptor) mutations can be inhibited by specific tyrosine kinase inhibitors (TKIs), which have changed the landscape of lung cancer therapy. However, due to secondary mutations and bypass receptors, such as AXL (AXL receptor tyrosine kinase), drug resistance eventually emerges in most patients treated with the first-, second-, or third-generation TKIs (e.g., osimertinib). To inhibit AXL and resistance to osimertinib, we compare two anti-AXL drugs, an antibody (mAb654) and a TKI (bemcentinib). While no pair of osimertinib and an anti-AXL drug is able to prevent relapses, triplets combining osimertinib, cetuximab (an anti-EGFR antibody), and either anti-AXL drug are initially effective. However, longer monitoring uncovers superiority of the mAb654-containing triplet, possibly due to induction of receptor endocytosis, activation of immune mechanisms, or disabling intrinsic mutators. Hence, we constructed a bispecific antibody that engages both AXL and EGFR. When combined with osimertinib, the bispecific antibody consistently inhibits tumor relapses, which warrants clinical trials. |
| 巻・号 | 5(9) |
| ページ | 101703 |
| 公開日 | 2024-9-17 |
| DOI | 10.1016/j.xcrm.2024.101703 |
| PII | S2666-3791(24)00424-5 |
| PMID | 39216477 |
| MeSH | Acrylamides* / pharmacology Aniline Compounds* / pharmacology Aniline Compounds* / therapeutic use Animals Antibodies, Bispecific* / pharmacology Axl Receptor Tyrosine Kinase* Cell Line, Tumor Cetuximab / pharmacology Cetuximab / therapeutic use Drug Resistance, Neoplasm* / drug effects Drug Resistance, Neoplasm* / genetics ErbB Receptors* / antagonists & inhibitors ErbB Receptors* / genetics ErbB Receptors* / metabolism Female Humans Indoles Lung Neoplasms / drug therapy Lung Neoplasms / genetics Lung Neoplasms / pathology Mice Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use Proto-Oncogene Proteins* / antagonists & inhibitors Proto-Oncogene Proteins* / genetics Proto-Oncogene Proteins* / metabolism Pyrimidines Receptor Protein-Tyrosine Kinases* / antagonists & inhibitors Receptor Protein-Tyrosine Kinases* / genetics Receptor Protein-Tyrosine Kinases* / immunology Xenograft Model Antitumor Assays |
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 12 |
| 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 | |
| 遺伝子材料 | tFucci(CA)2/pCSII-EF (RDB15446) |