Evidence map›Paper›PMID 42160004›Full record

ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2026

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 and 6 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors.

Aochu LiuSino-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.
Zhenguo LiuDepartment of Thoracic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
Lizhen JiangSino-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.
Andong HuangSino-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.ORCID https://orcid.org/0009-0007-6703-700X
Xinqing LinThe 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.
Xinyue LiSino-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.
Bingyuan LiuSino-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.
Shiwen HuSino-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.
Qiang PanSino-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.
Junjun HuangGuangzhou 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.
Liyuan YinLung Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Liling JiangSino-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.
Wei YiGuangzhou 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.
Wenjun MaoDepartment 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.ORCID https://orcid.org/0000-0002-4644-9749
Yueyuan ZhengClinical Big Data Research Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China.
Xianping ShiSino-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.ORCID https://orcid.org/0000-0002-5774-8568

Funding

Guangdong Basic and Applied Basic Research Foundation 2024A1515010703Guangxi Natural Science Foundation Program 2025GXNSFAA069235National Natural Science Foundation of China 32570794Natural Science Foundation of Guangdong Province 2025A1515012520Natural Science Foundation of Guangdong Province 2026A1515010452Shenzhen Medical Research Fund B2402019
6 · The paper itself

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.

Indexed as

AcrylamidesAniline CompoundsCarcinoma, Non-Small-Cell LungChromatinDrug Resistance, NeoplasmLung NeoplasmsAnimalsAntineoplastic AgentsCell Line, TumorEndothelial PAS Domain-Containing Protein 1Gene Expression Regulation, NeoplasticHumansIndolesMicePyrimidinesAcrylamidesAniline CompoundsAntineoplastic AgentsChromatinEndothelial PAS Domain-Containing Protein 1IndolesosimertinibPyrimidinescore regulatory circuitferroptosisID3neuroendocrine differentiationnon‐small cell lung cancerosimertinib resistancesuper‐enhancer

Identifiers

PMID42160004
PMCPMC13335962

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.