Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer
Fernando J. de Miguel, Claudia Gentile, William W. Feng, Shannon J. Silva, Akshay Sankar, Francisco Expósito, Wesley L. Cai, Mary Ann Melnick, Camila Robles-Oteíza, Madeline M. Hinkley, Jeanelle A. Tsai, Antja-Voy Hartley, Jin Wei, Anna Wurtz, Fangyong Li, Maria Toki, David L. Rimm, Robert Homer, Craig B. Wilen, Andrew Xiao, Jun Qi, Qin Yan, Don X. Nguyen, Pasi A. Jänne, Cigall Kadoch, Katerina Politi
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.