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

Andreas I Papadakis1, Chong Sun2, Theo A Knijnenburg3

  • 1Department of Biochemistry, The Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, QC H3G 1Y6, Canada.

Cell Research
|February 7, 2015
PubMed

Insights

Loss of the SWI/SNF chromatin remodeler SMARCE1 boosts EGFR expression, causing resistance to MET and ALK inhibitors in lung cancer. Targeting EGFR can restore sensitivity in these tumors.

Area of Science:

  • Oncology
  • Cancer Biology
  • Epigenetics

Background:

  • SWI/SNF chromatin remodeling complexes are crucial tumor suppressors, with recurrent mutations found across various cancers.
  • Dysregulation of chromatin remodeling impacts oncogenic signaling pathways, contributing to cancer development.
  • Specific components like SMARCE1 play roles in maintaining cellular homeostasis and suppressing tumor growth.

Purpose of the Study:

  • To investigate the functional role of SMARCE1 in non-small cell lung cancer (NSCLC).
  • To determine the impact of SMARCE1 loss on epidermal growth factor receptor (EGFR) expression and drug sensitivity.
  • To explore potential therapeutic strategies for SMARCE1-deficient NSCLCs.

Main Methods:

  • Utilized knockdown models to assess SMARCE1 function in NSCLC cells.
  • Analyzed EGFR expression levels in response to SMARCE1 modulation.
  • Investigated the binding of SMARCE1 to the EGFR locus using chromatin immunoprecipitation assays.
  • Assessed the impact of SMARCE1 loss on sensitivity to MET, ALK, and EGFR inhibitors.

Main Results:

  • SMARCE1 loss was found to induce EGFR expression in NSCLCs.
  • Loss of SMARCE1 conferred resistance to MET and ALK inhibitors.
  • SMARCE1 directly binds to regulatory regions of the EGFR gene, suppressing its transcription partly via CBX2 regulation.
  • Inhibition of EGFR with gefitinib restored sensitivity to MET and ALK inhibitors in SMARCE1-deficient cells.

Conclusions:

  • SMARCE1 acts as a tumor suppressor in NSCLC by regulating EGFR expression.
  • SMARCE1 deficiency leads to resistance against MET and ALK inhibitors through EGFR upregulation.
  • Targeting EGFR offers a viable therapeutic strategy for NSCLCs with SMARCE1-deficient tumors.

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