Epigenomic analysis identifies DTP subpopulation using HOPX to develop targeted therapy resistance in lung adenocarcinoma

Genomic studies have identified oncogenic drivers in lung cancer, enabling effective targeted therapies. However, patients who initially respond inevitably experience regrowth. The drug-tolerant persister (DTP) stage is a key source of non-genetic resistance, yet its epigenetic regulation remains unclear. Using single-cell chromatin accessibility profiling (scATAC-seq), we identified two distinct DTP subpopulations in EGFR- and KRAS-inhibited models. The integrative network and pathway analysis revealed that one subpopulation is associated with cell cycle, while the other is enriched in developmental pathways. HOPX was the most enriched alveolar signature gene in the latter. It was transiently upregulated with cytoplasmic-to-nuclear translocation, and its deletion significantly delayed DTP regrowth. Mechanistically, HOPX regulates NF-κB activation and repressive histone modifications. Combining targeted therapy with NF-κB or histone-methyltransferase inhibitors nearly abolished DTP regrowth. These findings highlight a potential anti-relapse strategy by targeting developmental pathways to modulate key lineage factors during lung regeneration in patients relapsing on targeted therapy.