SMARCE1 suppresses EGFR expression and controls responses to MET and ALK inhibitors in lung cancer

Cell Res. 2015 Apr;25(4):445-58. doi: 10.1038/cr.2015.16. Epub 2015 Feb 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Chromosomal Proteins, Non-Histone / biosynthesis
  • Chromosomal Proteins, Non-Histone / genetics*
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / biosynthesis*
  • ErbB Receptors / genetics
  • Gefitinib
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Mutation
  • Polycomb Repressive Complex 1 / biosynthesis
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / genetics
  • Quinazolines / administration & dosage
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics
  • Signal Transduction / drug effects

Substances

  • CBX2 protein, human
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Quinazolines
  • SMARCE1 protein, human
  • Polycomb Repressive Complex 1
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • EGFR protein, human
  • ErbB Receptors
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Receptor Protein-Tyrosine Kinases
  • Gefitinib