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<p>Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), has dramatically transformed the treatment landscape for patients with <i>EGFR</i>-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 <i>EGFR</i>-mutant cells. Our findings reveal a robust concordance between epigenetic regulome and transcriptomic changes that characterize the osimertinib resistant state. Through 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 <i>cis</i>-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. These findings provide novel insights into the epigenetic and transcriptional control of osimertinib resistance in <i>EGFR</i>-mutant NSCLC, highlighting AP-1 as a targetable vulnerability of resistance-related hallmarks and offering a promising avenue for developing resistance reversal strategies.</p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月25日

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  • Bengisu Dayanc,
  • Sude Eris,
  • Nazife Ege Gulfirat,
  • Gulden Ozden-Yilmaz,
  • Ece Cakiroglu,
  • Ozlem Silan Coskun Deniz,
  • Gökhan Karakülah,
  • Serap Erkek-Ozhan,
  • Serif Senturk

摘要

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. Through 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. These 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.