RRC ID 76706
Author 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.
Title L858R emerges as a potential biomarker predicting response of lung cancer models to anti-EGFR antibodies: Comparison of osimertinib vs. cetuximab.
Journal 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.
Pages 101142
Published 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
Resource
Human and Animal Cells II-18(RCB2093)
DNA material tFucci(CA)2/pCSII-EF (RDB15446)