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]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1167201 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30837060_1.fastq.gz | Fastqsanger.gz | |||
| SRR30837060_2.fastq.gz | Fastqsanger.gz | |||
| SRR30837061_1.fastq.gz | Fastqsanger.gz | |||
| SRR30837061_2.fastq.gz | Fastqsanger.gz | |||
| SRR30837062_1.fastq.gz | Fastqsanger.gz |
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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.
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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.
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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.
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Project description:Integrative multi-omics identifies AP-1 transcription factor as a targetable mediator of acquired osimertinib resistance in non-small cell lung cancer
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Project description:Systemic hypertension increases cardiac workload and subsequently induces signaling networks in heart that underlie myocyte growth (hypertrophic response) through expansion of sarcomeres with the aim to increase contractility. However, conditions of increased workload can induce both adaptive and maladaptive growth of heart muscle. Previous studies implicate two members of the AP-1 transcription factor family, junD and fra-1, in regulation of heart growth during hypertrophic response. In this study, we investigate the function of the AP-1 transcription factors, c-jun and c-fos, in heart growth. Using pressure overload-induced cardiac hypertrophy in mice and targeted deletion of Jun or Fos in cardiomyocytes, we show that c-jun is required for adaptive cardiac hyphertrophy, while c-fos is dispensable in this context. c-jun promotes expression of sarcomere proteins and suppresses expression of extracellular matrix proteins. Capacity of cardiac muscle to contract depends on organization of principal thick and thin filaments, myosin and actin, within the sarcomere. In line with decreased expression of sarcomere-associated proteins, Jun-deficient cardiomyocytes present disarrangement of filaments in sarcomeres and actin cytoskeleton disorganization. Moreover, Jun-deficient hearts subjected to pressure overload display pronounced fibrosis and increased myocyte apoptosis finally resulting in dilated cardiomyopathy. In conclusion, c-jun but not c-fos is required to induce a transcriptional program aimed at adapting heart growth upon increased workload. Microarrays were used to identify specific genes that might be globally affected in the absence of c-jun in cardiomyocytes. Total RNA was extracted from the hearts of 10 weeks old Junf/f (n=2) and Jun delta mu (n=2) mice using TRIzol Reagent.
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