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Super-enhancer–mediated SMAD3–NR2F2–ID3 transcriptional complex orchestrates Osimertinib resistance in non-small cell lung cancer [CUT&Tag]

ABSTRACT: Osimertinib resistance remains a major challenge in the treatment of non–small cell lung cancer (NSCLC). Here, we identify an unconventional super-enhancer–driven transcriptional module, composed of SMAD3, NR2F2, and ID3, in which ID3 functions as a transcriptional co-factor to sustain resistance. Mechanistically, ID3 directly interacts with SMAD3 and NR2F2, inducing conformational rearrangements that enhance their DNA-binding affinity to enhancer regions, thereby increasing transcriptional activity. This ID3-SMAD3/NR2F2 complex selectively activates EPAS1, which in turn promotes neuroendocrine differentiation and suppresses ferroptosis, thereby maintaining the resistant phenotype. Disruption of this complex abrogates EPAS1 expression and restores Osimertinib sensitivity in preclinical models. Our findings uncover a previously unrecognized role of ID3 as a transcriptional co-factor and highlight the super-enhancer–driven SMAD3–NR2F2–ID3–EPAS1 axis as a promising therapeutic target to overcome Osimertinib resistance in NSCLC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308412 | GEO | 2026/07/15

REPOSITORIES: GEO

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Similar Datasets

Super-enhancer–mediated SMAD3–NR2F2–ID3 transcriptional complex orchestrates Osimertinib resistance in non-small cell lung cancer

Project description:Osimertinib resistance remains a major challenge in the treatment of non–small cell lung cancer (NSCLC). Here, we identify an unconventional super-enhancer–driven transcriptional module, composed of SMAD3, NR2F2, and ID3, in which ID3 functions as a transcriptional co-factor to sustain resistance. Mechanistically, ID3 directly interacts with SMAD3 and NR2F2, inducing conformational rearrangements that enhance their DNA-binding affinity to enhancer regions, thereby increasing transcriptional activity. This ID3-SMAD3/NR2F2 complex selectively activates EPAS1, which in turn promotes neuroendocrine differentiation and suppresses ferroptosis, thereby maintaining the resistant phenotype. Disruption of this complex abrogates EPAS1 expression and restores Osimertinib sensitivity in preclinical models. Our findings uncover a previously unrecognized role of ID3 as a transcriptional co-factor and highlight the super-enhancer–driven SMAD3–NR2F2–ID3–EPAS1 axis as a promising therapeutic target to overcome Osimertinib resistance in NSCLC.

2026-07-15 | GSE308413 | GEO

Super-enhancer–mediated SMAD3–NR2F2–ID3 transcriptional complex orchestrates Osimertinib resistance in non-small cell lung cancer [ChIP-seq]

2026-07-15 | GSE308411 | GEO

MUC1-C IS ESSENTIAL FOR ESTABLISHING AND RECALLING INFLAMMATORY MEMORY OF OSIMERTINIB RESISTANCE IN NSCLC CELLS [H1975_vs_H1975-OR]

Project description:MUC1-C is necessary for establishing and recalling resistance of NSCLC cells to osimertinib by driving an inflammatory memory responseThe oncogenic MUC1-C protein functions as a master regulator of NSCLC cell resistance to osimertinib by unclear mechanisms. We report that MUC1-C-mediated regulation of STAT1 and the interferon (IFN) type I/II pathways is necessary for establishing osimertinib resistance. Studies of osimertinib-resistant NSCLC cells selected for growth in the absence of drug further demonstrate that revertant cells are dependent on MUC1-C for recalling resistance to osimertinib. We show that establishing and recalling osimertinib resistance is dependent on activation of the MUC1 gene at (i) a proximal enhancer-like signature 1 (pELS-1) by MUC1-C and STAT1 and (ii) a pELS-2 by MUC1-C, JUN/AP-1 and PBAF. The MUC1 pELS regions function as memory domains for activation of MUC1-C and downstream STAT1 and IFN stimulated genes in conferring osimertinib resistance. Of clinical relevance, we report that the MUC1-C-driven inflammatory responses are induced in patient-derived, osimertinib-resistant MGH170 NSCLC cells with MET amplification. Our results further demonstrate that MGH170 cells are dependent on the MUC1-C-induced inflammatory response for resistance to the osimertinib and combination of osimertinib with the MET inhibitor capmatinib. These findings indicate that MUC1-C is necessary for establishing and recalling resistance of NSCLC cells to osimertinib by driving an inflammatory memory response.

2025-06-26 | GSE270995 | GEO

MUC1-C IS ESSENTIAL FOR ESTABLISHING AND RECALLING INFLAMMATORY MEMORY OF OSIMERTINIB RESISTANCE IN NSCLC CELLS [H1975-RT_vs_H1975-OR]

2025-06-26 | GSE270997 | GEO

Muc1-C Regulates Neat1 Lncrna Expresmuc1-C Is Essential For Establishing And Recalling Inflammatory Memory Of Osimertinib Resistance In Nsclc Cellssion And Paraspeckle Formation In Cancer Stem Cells

2025-04-02 | GSE263757 | GEO

The differential gene expression of the lung cancer cell line HCC827 before and after resistance to osimertinib

Project description:Osimertinib, as a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been approved as a first-line therapy in advanced non–small-cell lung cancer (NSCLC) patients with EGFR-activating or T790M resistance mutations. However, the efficacy of osimertinib is limited due to acquired resistance. In order to search for the mechanism of resistance to osimertinib, we screened on significantly upregulated genes encoding protein kinases in osimertinib-resistant NSCLC cells via RNA-sequence.In summary, our data elucidate the alterations in gene expression within lung cancer cells before and after resistance to osimertinib, aiding in the analysis and identification of key molecules influencing osimertinib resistance.

2024-03-30 | GSE262582 | GEO

Lipid metabolism drives osimertinib resistance in non-small cell lung cancer

Project description:Non-small-cell lung cancer (NSCLC) accounts for more than 80 % of lung cancer cases. Epidermal growth factor receptor mutations (EGFRm) occur in 15 % and 40 % of NSCLC in Western and Asian populations, respectively. Current treatment for advanced NSCLC targets EGFRm with tyrosine kinase inhibitors (TKIs). Osimertinib is a third generation EGFR-TKI now used as a first-line treatment in advanced/metastatic NSCLC, however drug resistance frequently develops. Dysregulation of metabolism has been suggested to play a role in development of drug resistance. Here, we investigated the role of lipid metabolism in the development of osimertinib resistance (OR) using pharmacologically-induced resistant cellular models. We used a multi-omics approach, combining lipidomics with proteomics analyses. We found alterations in processes relating to metabolism, including dysregulated sphingolipid metabolism, lipid peroxidation and ferroptosis. In particular, we identified that OR lines reduce free ceramides in favour of complex glycosphingolipids. Mechanistically, this metabolic shift avoids ceramide-mediated apoptosis via caspase 3 activation. Importantly, when we combined osimertinib with D-PDMP, an inhibitor of the key enzyme responsible for the conversion of ceramide to glucosylceramide, we increased sensitivity to osimertinib. Overall, we have identified the glycosphingolipid metabolic pathway as a potential therapeutic target to reinstate sensitivity to osimertinib in NSCLC.

2026-03-03 | PXD071008 | Pride

PKM2-deficiency induced fatty acid biosynthesis activation limits the response of non-small cell lung cancer to Osimertinib

Project description:Non-small cell lung cancer (NSCLC) - the most common form of lung cancer - is an aggressive malignancy with limited effective therapeutic options1. Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has revolutionized treatment for EGFR-mutant NSCLC, yet resistance significantly limits its clinical benefit to patients2. Here, using a genome-wide genetic screen, we discover that pyruvate kinase M2 (PKM2) is a novel regulator of Osimertinib resistance. Loss of PKM2 triggers fatty acid biosynthesis activation in a glycolysis-independent manner. We have shown that PKM2 interacts with KDM1A in cytosol and nuclear translocation of KDM1A is increased in both PKM2-KO and Osimertinib-persister cells. Mechanistically, KDM1A demethylates H3K9me3 in the promoter region of the key lipid synthesis enzyme, fatty acid synthase (FASN), and cooperates with transcription factor AP-2 to activate FASN transcription, thereby conferring Osimertinib resistance. Pharmacological inhibition of FASN by Orlistat induces synthetic lethality with Osimertinib in vitro and vivo Osimertinib-resistant models. Treatment of 9 NSCLC patients who were unresponsive to Osimertinib with the combination of Osimertinib plus Orlistat resulted in meaningful clinical responses. Our data highlights metabolic vulnerabilities and provides potential therapeutic approaches for treating TKI-resistant NSCLC.

2026-06-15 | GSE300311 | GEO

Homo sapiens

Project description:Osimertinib resistance in human NSCLC

| PRJNA736433 | ENA

CircROBO2 Orchestrates Osimertinib Resistance Through miR-625-5p/PDGFB-Mediated MAPK Activation in Non-Small Cell Lung Cancer

Project description:Background: The emergence of acquired resistance to osimertinib represents a formidable therapeutic challenge in the management of non-small cell lung cancer (NSCLC). While circular RNAs (circRNAs) have been increasingly recognized as crucial modulators of chemotherapeutic resistance, their specific involvement in osimertinib resistance mechanisms remains poorly elucidated. Methods: We established osimertinib-resistant NSCLC cell lines (HCC4006OR) through prolonged drug exposure and conducted comprehensive transcriptome sequencing to identify differentially expressed circRNAs. The molecular characteristics and functional implications of circROBO2 were systematically investigated utilizing an array of cellular and molecular biological methodologies. Advanced molecular dynamics simulations were implemented to elucidate the potential molecular interactions between PDGFB and osimertinib. Results: We identified circROBO2 as significantly upregulated in osimertinib-resistant HCC4006OR cells. Functional studies revealed that circROBO2 enhances cell survival, proliferation, and invasion while suppressing apoptosis under osimertinib treatment. Mechanistically, circROBO2 functions as a molecular sponge for miR-625-5p, resulting in elevated PDGFB expression and subsequent activation of the MAPK pathway, particularly the RAF/MEK/ERK cascade. Targeting this pathway through circROBO2 knockdown or miR-625-5p overexpression partially restored osimertinib sensitivity in resistant cells. Molecular dynamics simulations suggested potential direct interactions between PDGFB and osimertinib, providing additional insights into the resistance mechanism. Conclusions: Our study identifies a novel circROBO2/miR-625-5p/PDGFB regulatory axis in osimertinib resistance and positions circROBO2 as a potential therapeutic target and biomarker for NSCLC treatment.

2026-06-30 | GSE301232 | GEO

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