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Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer

ABSTRACT: Acquired resistance to tyrosine kinase inhibitors, such as Osimertinib used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-mutational mechanisms. Here, we generate and comprehensively characterize the chromatin accessibility and gene regulatory signatures of pairs of parental and Osimertinib-resistant EGFR-mutant cell lines. Specifically, we profile the genome-wide localization of mSWI/SNF chromatin remodeling complexes in these cell line pairs, identifying both pan-cell and tumor cell-specific gene targets underlying the resistance state. Importantly, genetic and small molecule-based pharmacologic disruption of the SMARCA4/SMARCA2 mSWI/SNF ATPases re-sensitizes a subset of resistant cell lines and in vivo tumor models to Osimertinib. This re-sensitization is linked to mSWI/SNF-mediated regulation of cell proliferative, epithelial to mesenchymal transition, and epithelial cell differentiation-related programs, as well as NRF2 signaling. These data highlight the role for mSWI/SNF complexes in supporting TKI resistance and suggest potential utility of mSWI/SNF inhibitors in TKI-resistant lung cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227999 | GEO | 2023/09/15

REPOSITORIES: GEO

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Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer

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