Reprogramming resistance in advanced lung cancer: epigenetic modulation to restore therapeutic vulnerability.

Abstract

Lung cancer is the most prevalent cancer and cause of death; most patients present themselves at an advanced stage and continuously acquire resistance to targeted agents, antibody-drug conjugates, chemotherapy, and immune checkpoint inhibitors. In addition to secondary mutations, epigenetically driven cellular plasticity, including DNA methylation, histone modification, chromatin remodeling, RNA (m 6A)-marks, and non-coding RNAs, facilitates resistance coordination, EMT/drug-tolerant persisters, lineage switching (e.g., NSCLC to NSCLC), bypass signaling, and immune evasion by tumor cells. These states can be therapeutically rewired by epigenetic drugs: low-dose DNMT/HDAC priming restores silenced tumor-suppressor and antigen-presentation genes and activates viral-mimicry interferon signaling to augment checkpoint blockade; EZH2 and LSD1 inhibitors target plasticity and neuroendocrine programs; BET inhibition suppresses adaptive transcription; CBP/p300 modulators suppress NRF2-dependent redox survival; Combination therapies exploiting synthetic lethality through PRMT5 inhibition, applied rationally with TKIs, ICIs, chemotherapy, and antibody-drug conjugates (ADCs), are currently under clinical investigation. Biomarker-directed patient selection (e.g., MTAP loss clustering, EZH2/LSD1 activity, methylation and chromatin signatures, and liquid biopsy dynamics of methylation or ctDNA) will be critical to enrich for patients most likely to benefit. In the future, better optimized sequencing using short priming windows, intermittent dosing, and future readouts of prospective pharmacodynamics could transform transient re-sensitization into lasting control. This study aims to critically appraise mechanistic and clinical evidence linking epigenetic plasticity to therapy resistance in advanced lung cancer and to propose biomarker-directed epigenetic combination and sequencing strategies to restore drug sensitivity.

Key Findings

• Epigenetic mechanisms such as DNA methylation, histone modification, chromatin remodeling, RNA m6A marks, and non-coding RNAs contribute to therapy resistance in advanced lung cancer.
• Epigenetic drugs including DNMT/HDAC inhibitors, EZH2 and LSD1 inhibitors, BET inhibitors, and CBP/p300 modulators can reprogram resistant cancer cells and restore therapeutic vulnerability.
• Combination therapies targeting epigenetic plasticity alongside TKIs, immune checkpoint inhibitors, chemotherapy, and antibody-drug conjugates show promise and are under clinical investigation.

Clinical Significance

Citation

He Fang, Moawad Mostafa Hossam El Din, Alsaied Mohamed Aet al.. Reprogramming resistance in advanced lung cancer: epigenetic modulation to restore therapeutic vulnerability. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2026-Mar-22.