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Integrative multi-omics identifies AP-1 transcription factor as a targetable mediator of acquired osimertinib resistance in non-small cell lung cancer [RNA_SEQ_HCC827 OsiR]

ABSTRACT: Integrative multi-omics identifies AP-1 transcription factor as a targetable mediator of acquired osimertinib resistance in non-small cell lung cancer [RNA_SEQ_HCC827 OsiR]

PROVIDER: PRJNA1166123 | ENA |

REPOSITORIES: ENA

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			Action	DRS
		Other
	SRR30817353_1.fastq.gz	Fastqsanger.gz
	SRR30817353_2.fastq.gz	Fastqsanger.gz
	SRR30817355_1.fastq.gz	Fastqsanger.gz
	SRR30817355_2.fastq.gz	Fastqsanger.gz

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Integrative multi-omics identifies AP-1 transcription factor as a targetable mediator of acquired osimertinib resistance in non-small cell lung cancer [ATAC-SEQ]

Project description:Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), has dramatically transformed the treatment landscape for patients with EGFR-mutant NSCLC. However, the long-term success of this therapy is often compromised by the onset of acquired resistance, with non-genetic mechanisms increasingly recognized as pivotal contributors. Here, we exploit a multi-omics approach to profile genome-wide chromatin accessibility and transcriptional landscapes between drug sensitive and resistant EGFR-mutant cells. Our findings reveal a robust concordance between epigenetic regulome and transcriptomic changes that characterize the osimertinib resistant state. Using CRISPR-based functional genomics screen targeting epigenetic regulators and transcription factors, we uncover a critical regulatory network featuring key members of the NuRD and PRC2 complexes that mediate resistance. Most critically, our screen identifies FOSL1 and JUN, two subunits of the AP-1 transcription factor within this network, as the most significant hits. Mechanistically, we demonstrate that cis-regulatory elements exhibiting altered chromatin accessibility in the resistant state are enriched for cognate AP-1 binding motifs, enabling AP-1 to orchestrate a gene expression program that underpins the druggable MEK/ERK signaling axis, potentially enhancing cell viability and fitness of resistant cells. Importantly, genetic depletion or pharmacological inhibition of AP-1 reinstates cellular and molecular sensitivity and reverts resistance-associated phenotypes, such as epithelial-to-mesenchymal transition, upon anti-EGFR rechallenge by repressing AKT and ERK signaling. The findings provide novel insights into the epigenetic and transcriptional control of osimertinib resistance in EGFR-mutant NSCLC, highlighting AP-1 as a targetable vulnerability of resistance-related hallmarks and offering a promising avenue for developing resistance reversal strategies.

2025-05-27 | GSE278221 | GEO

Integrative multi-omics identifies AP-1 transcription factor as a targetable mediator of acquired osimertinib resistance in non-small cell lung cancer [RNA_SEQ_HCC827 OsiR]

2025-05-27 | GSE278222 | GEO

Integrative multi-omics identifies AP-1 transcription factor as a targetable mediator of acquired osimertinib resistance in non-small cell lung cancer [RNA_SEQ_FOSL1 and JUN KO]

2025-05-27 | GSE278409 | GEO

Integrative multi-omics identifies AP-1 transcription factor as a targetable mediator of acquired osimertinib resistance in non-small cell lung cancer

Project description:Integrative multi-omics identifies AP-1 transcription factor as a targetable mediator of acquired osimertinib resistance in non-small cell lung cancer

| PRJNA1256437 | ENA

Integrative multi-omics identifies AP-1 transcription factor as a targetable mediator of acquired osimertinib resistance in non-small cell lung cancer [ATAC-SEQ]

Project description:Integrative multi-omics identifies AP-1 transcription factor as a targetable mediator of acquired osimertinib resistance in non-small cell lung cancer [ATAC-SEQ]

| PRJNA1166108 | ENA

Integrative multi-omics identifies AP-1 transcription factor as a targetable mediator of acquired osimertinib resistance in non-small cell lung cancer [RNA_SEQ_FOSL1 and JUN KO]

Project description:Integrative multi-omics identifies AP-1 transcription factor as a targetable mediator of acquired osimertinib resistance in non-small cell lung cancer [RNA_SEQ_FOSL1 and JUN KO]

| PRJNA1167201 | ENA

Acquired Resistance Mechanisms to Osimertinib in EGFR Mutant Lung Cancer

Project description:Acquired Resistance Mechanisms to Osimertinib in EGFR Mutant Lung Cancer

| PRJNA616047 | ENA

Acquired Resistance Mechanisms to Osimertinib in EGFR Mutant Lung Cancer

Project description:Acquired Resistance Mechanisms to Osimertinib in EGFR Mutant Lung Cancer

| PRJNA616048 | ENA

Integrative multi-omics identifies AP-1 transcription factor as a targetable mediator of acquired osimertinib resistance in non-small cell lung cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-05-27 | GSE295823 | 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

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