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Inactivating mutations of SMARCE1 promotes EGFR expression and suppress the responses to MET and ALK inhibitors in lung cancer

 

The loss-of-function mutations in components of SWI/SNF chromatin-remodeling complexes are associated with the progression of multiple cancers and the resistance to some anti-tumor drugs. The findings indicates that SWI/SNF chromatin-remodeling complexes play key roles in regulating oncogenic signaling pathways as tumor suppressors. The study conducted by Papadakis et al. showed inactivating mutations in SMARCE1 gene, which encodes SWI/SNF subunit, upregulate EGFR expression and induce resistance to MET and ALK inhibitors in non-small cell lung cancers (NSCLCs). The article was published in Cell Research.

 

Several studies have proved the tumor suppressor role of the SWI/SNF complexes, however, the molecular mechanisms of how do SWI/SNF components regulate malignant transformation, and how do they mediate oncogenic signaling are currently largely unknown. By using functional genetic screens, researchers examined genes that mediate drug responses to MET inhibition, and found a candidate gene, SMARCE1.  This gene, also known as BAF57, encodes SWI/SNF component and its inactivation confers resistance to MET and ALK inhibitors by promoting EGFR expression in NSCLCS. Mechanically, SMARCE1 suppresses EGFR expression by binding to regulatory regains of gene locus ,and regulating expression of CBX2, a component of Polycomb Repressive Complex. In addition, the EGFR inhibitor gefitinib restores the sensitivity to MET and ALK inhibitors in SMARCE1-knowckdown cells with NSCLCs. The findings reveal the molecular mechanism in regulation of oncogenic signaling pathways by SMARCE1, indicating it as a potential target for therapeutic strategy against NSCLCs.

 

Reference:
Cell Res. 2015 Feb 6. doi: 10.1038/cr.2015.16.

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