journal article·2026-05-20Open access

A Non‐Canonical Core Transcriptional Regulatory Circuit Orchestrates Chromatin Reprogramming to Drive Osimertinib Resistance in Non‐Small Cell Lung Cancer

Aochu Liu, Zhenguo Liu, Lizhen Jiang, Andong Huang, Xinqing Lin, Xinyue Li, Bingyuan Liu, Shiwen Hu, Qiang Pan, Junjun Huang, Liyuan Yin, Liling Jiang, Wei Yi, Wenjun Mao, Yueyuan Zheng, Xianping Shi

Abstract

ABSTRACT Osimertinib resistance represents a major therapeutic challenge in non‐small cell lung cancer (NSCLC), yet the underlying epigenetic mechanisms remain incompletely understood. Through integrated epigenomic and transcriptomic profiling, we identified a resistance‐specific, non‐canonical transcriptional circuit driven by the coordinated action of three core components: ID3, SMAD3, and NR2F2. These transcription factors form protein complexes that co‐bind to shared enhancers or promoters, reciprocally enhancing each other's transcriptional activity and that of their downstream targets. Mechanistically, ID3 mediates the chromatin residence of the SMAD3‐NR2F2 complex through its non‐canonical function as a structural co‐factor. This rewires the transcriptional program of resistant cells to ultimately drive resistance via direct upregulation of HIF2A, a dual‐function hub that concurrently promotes neuroendocrine differentiation and suppresses ferroptosis. Functional studies confirmed that disrupting this circuit or inhibiting its downstream effector HIF2A restored Osimertinib sensitivity in resistant models. Our study elucidates a novel epigenetic paradigm through which a non‐canonical, self‐reinforcing transcriptional circuit co‐opts lineage plasticity and cell death evasion to drive Osimertinib resistance, thereby establishing a therapeutically actionable target for overcoming this aggressive phenotype.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Ferroptosis and cancer prognosis · Chromatin Remodeling and Cancer · TGF-β signaling in diseases

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Sino‐French Hoffmann Institute Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation School of Basic Medical Sciences Guangzhou Medical University Guangzhou Guangdong China

The Affiliated Traditional Chinese Medicine Hospital Guangzhou Medical University Guangzhou Guangdong China

Department of Thoracic Surgery The First Affiliated Hospital of Sun Yat‐Sen University Guangzhou Guangdong China

The First Affiliated Hospital of Guangzhou Medical University National Center for Respiratory Medicine National Clinical Research Center for Respiratory Disease State Key Laboratory of Respiratory Disease Guangzhou Institute of Respiratory Health Guangzhou China

Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology the NMPA and State Key Laboratory of Respiratory Disease School of Pharmaceutical Sciences Guangzhou Medical University Guangzhou China

Lung Cancer Center West China Hospital Sichuan University Chengdu China

Department of Cardiothoracic Surgery Wuxi Medical Center the Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Nanjing Medical University Wuxi China

Wuxi College of Clinical Medicine Nanjing Medical University Wuxi China

Clinical Big Data Research Center Scientific Research Center The Seventh Affiliated Hospital of Sun Yat‐Sen University Shenzhen Guangdong China

Funding

Natural Science Foundation of Guangdong Province · Basic and Applied Basic Research Foundation of Guangdong Province · National Natural Science Foundation of China

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