| 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
|
| 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) |
