SMARCE1 suppresses EGFR expression and controls responses to MET and ALK inhibitors in lung cancer
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Publication date
2015-04
Authors
Papadakis, Andreas I
Sun, Chong
Knijnenburg, Theo A
Xue, Yibo
Grernrum, Wipawadee
Hölzel, Michael
Nijkamp, Wouter
Wessels, Lodewyk F A
Beijersbergen, Roderick L
Bernards, R
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Article
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Abstract
Recurrent inactivating mutations in components of SWI/SNF chromatin-remodeling complexes have been identified across cancer types, supporting their roles as tumor suppressors in modulating oncogenic signaling pathways. We report here that SMARCE1 loss induces EGFR expression and confers resistance to MET and ALK inhibitors in non-small cell lung cancers (NSCLCs). We found that SMARCE1 binds to regulatory regions of the EGFR locus and suppresses EGFR transcription in part through regulating expression of Polycomb Repressive Complex component CBX2. Addition of the EGFR inhibitor gefitinib restores the sensitivity of SMARCE1-knockdown cells to MET and ALK inhibitors in NSCLCs. Our findings link SMARCE1 to EGFR oncogenic signaling and suggest targeted treatment options for SMARCE1-deficient tumors.
Keywords
Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, Mutation, Polycomb Repressive Complex 1, Proto-Oncogene Proteins c-met, Quinazolines, Receptor Protein-Tyrosine Kinases, Receptor, Epidermal Growth Factor, Signal Transduction, EGFR signaling, drug resistance, RNAi screening
Citation
Papadakis, A I, Sun, C, Knijnenburg, T A, Xue, Y, Grernrum, W, Hölzel, M, Nijkamp, W, Wessels, L F A, Beijersbergen, R L, Bernards, R & Huang, S 2015, 'SMARCE1 suppresses EGFR expression and controls responses to MET and ALK inhibitors in lung cancer', Cell Research, vol. 25, no. 4, pp. 445-458. https://doi.org/10.1038/cr.2015.16