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

Andreas I Papadakis; Chong Sun; Theo A Knijnenburg; Yibo Xue; Wipawadee Grernrum; Michael Hölzel; Wouter Nijkamp; Lodewyk F A Wessels; Roderick L Beijersbergen; Rene Bernards; Sidong Huang

doi:10.1038/cr.2015.16

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.

Affiliations

¹ Department of Biochemistry, The Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, QC H3G 1Y6, Canada.
² Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
³ 1] Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands [2] Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109-5234, USA.
⁴ 1] Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands [2] Current address: Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany.

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

Grants and funding

MOP-130540/Canadian Institutes of Health Research/Canada