The histone-modified landscape: Core mechanisms of osimertinib resistance in EGFR-mutant lung cancer

Abstract

Despite the transformative impact of osimertinib as a cornerstone targeted therapy for advanced EGFR-mutant non-small cell lung cancer, the emergence of acquired resistance ultimately limits its long-term efficacy. While genetic alterations, tumor microenvironment dynamics, and cancer stem cells contribute to resistance, they inadequately explain its rapid adaptive evolution. This critical knowledge gap points to an underexplored dimension of resistance: the dynamic reprogramming of the epigenetic landscape. This review establishes dynamic histone plasticity--driven by imbalances in key epigenetic modifications such as acetylation and methylation, along with newly recognized marks including lactylation--as a pivotal epigenetic driver of resistance. Evidence demonstrates that these modifications remodel chromatin architecture, reprogram transcriptional networks, compromise DNA damage repair, and stabilize a drug-tolerant persister state, collectively accelerating tumor adaptation during therapeutic pressure. Beyond mechanism, distinct histone-modification signatures are emerging as promising predictive biomarkers for resistance, simultaneously revealing novel, pharmacologically targetable epigenetic vulnerabilities. Leveraging next-generation technologies, we propose an integrated strategy: multimodal epigenetic therapies combined with real-time liquid biopsy profiling to shift from reactive management toward predictive prevention of resistance. By bridging deep epigenomic mechanistic understanding with innovative diagnostic and therapeutic tools, this roadmap provides a proactive, adaptive framework designed to circumvent tumor evolutionary pathways, overcome therapeutic resistance, and prolong patient survival.