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Epigenomic analysis identifies DTP subpopulation using HOPX to develop targeted therapy resistance in lung
Yang Tian1,2, Reshmee Bhattacharya1,2, Seungyeul Yoo3,4,5
1Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Abstract:
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.
Insights
Drug-tolerant persister cells in lung cancer exhibit epigenetic regulation. Targeting developmental pathways and HOPX can prevent relapse by inhibiting lung cancer regeneration.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Genomic studies identified oncogenic drivers in lung cancer, leading to targeted therapies.
- Despite initial response, patients inevitably experience tumor regrowth due to drug-tolerant persister (DTP) cells.
- The epigenetic regulation of DTPs, a source of non-genetic resistance, remains poorly understood.
Purpose of the Study:
- To investigate the epigenetic mechanisms driving drug-tolerant persister (DTP) cell survival in lung cancer.
- To identify distinct DTP subpopulations and their regulatory pathways.
- To explore potential therapeutic strategies targeting DTPs to prevent cancer relapse.
Main Methods:
- Single-cell chromatin accessibility profiling (scATAC-seq) was employed to analyze DTPs.
- Integrative network and pathway analysis was performed to identify key molecular pathways.
- Gene deletion and drug inhibition studies were conducted to validate findings.
Main Results:
- Two distinct DTP subpopulations were identified: one linked to cell cycle, the other to developmental pathways.
- HOPX, an alveolar signature gene, was enriched in the developmental subpopulation and its deletion delayed DTP regrowth.
- HOPX regulates NF-κB activation and histone modifications, and combined inhibition nearly abolished DTP regrowth.
Conclusions:
- Epigenetic regulation, particularly involving HOPX and developmental pathways, is crucial for DTP survival in lung cancer.
- Targeting HOPX, NF-κB, or histone methyltransferases alongside standard therapies offers a potential strategy to prevent relapse.
- Modulating lung regeneration pathways presents a novel anti-relapse approach for patients with lung cancer.
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