Mechanisms of acquired resistance to osimertinib in EGFR T790M-Positive lung adenocarcinoma

Abstract

Background Third-generation epidermal growth factor receptor tyrosine kinase inhibitor osimertinib serves as the gold standard therapy for treating NSCLC patients harboring EGFR T790M mutations. The clinical utility of this agent, however, faces considerable constraints due to the unavoidable emergence of acquired resistance mechanisms. Understanding the molecular basis of osimertinib resistance holds paramount importance for determining optimal follow-up treatment approaches. Methods Clinical information from 86 lung adenocarcinoma patients carrying EGFR T790M mutations who showed disease advancement following osimertinib therapy was examined retrospectively, spanning the period from January 2018 through December 2023. Genomic characterization was conducted via next-generation sequencing on tissue or liquid biopsy specimens collected after resistance developed. Protein expression alterations were assessed through immunohistochemical staining, while critical resistance pathways underwent validation using cell line models. Results Among the 86-patient cohort, the median duration before disease progression reached 14.2 months. Genomic characterization identified these predominant resistance pathways: C797S mutations in EGFR (23.3%), amplification of MET (15.1%), amplification of HER2 (8.1%), mutations in PIK3CA (7.0%), transformation to small cell lung cancer (9.3%), and epithelial-mesenchymal transition (12.8%). Concurrent presence of multiple resistance mechanisms was detected in 24.4% of the patient population. Within the C797S mutation subset, 65.0% exhibited C797S/T790M in cis arrangement, 30.0% demonstrated trans arrangement, and 5.0% showed mixed configurations. Laboratory validation established that MET amplification confers resistance via bypass activation of both ERK and AKT signaling cascades. The poorest clinical outcomes were observed among patients undergoing histological transformation (median overall survival from confirmed progression: 8.3 months). Conclusion Remarkable heterogeneity characterizes the resistance mechanisms emerging against osimertinib in EGFR T790M-positive lung adenocarcinoma, with EGFR secondary mutations, bypass signaling pathway activation, and histological transformation representing the primary categories. Detection of specific resistance mechanisms enables tailored subsequent therapeutic approaches, with potential outcome improvements achievable through combination strategies incorporating targeted agents or immunotherapy.