Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Cancer Cell ; 41(8): 1516-1534.e9, 2023 08 14.
Article in English | MEDLINE | ID: mdl-37541244

ABSTRACT

Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility and gene regulatory signatures of osimertinib sensitive and resistant EGFR-mutant cell and patient-derived models and uncover a role for mammalian SWI/SNF chromatin remodeling complexes in TKI resistance. By profiling mSWI/SNF genome-wide localization, we identify both shared and cancer cell line-specific gene targets underlying the resistant state. Importantly, genetic and pharmacologic disruption of the SMARCA4/SMARCA2 mSWI/SNF ATPases re-sensitizes a subset of resistant models to osimertinib via inhibition of mSWI/SNF-mediated regulation of cellular programs governing cell proliferation, epithelial-to-mesenchymal transition, epithelial cell differentiation, and NRF2 signaling. These data highlight the role of mSWI/SNF complexes in supporting TKI resistance and suggest potential utility of mSWI/SNF inhibitors in TKI-resistant lung cancers.


Subject(s)
Lung Neoplasms , Animals , Humans , Chromatin Assembly and Disassembly , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Chromatin , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , ErbB Receptors/genetics , Mutation , Mammals/genetics , DNA Helicases/genetics , Nuclear Proteins/genetics , Transcription Factors/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...