title: SMARCE1 suppresses EGFR expression and controls responses to MET and ALK inhibitors in lung cancer.
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.
authors: Department of Biochemistry, The Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, QC H3G 1Y6, Canada.
authors: Andreas I
authors: AI
authors: Papadakis
authors: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: Chong
authors: C
authors: Sun
authors: 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.
authors: Theo A
authors: TA
authors: Knijnenburg
authors: Department of Biochemistry, The Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, QC H3G 1Y6, Canada.
authors: Yibo
authors: Y
authors: Xue
authors: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: Wipawadee
authors: W
authors: Grernrum
authors: 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.
authors: Michael
authors: M
authors: Hölzel
authors: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: Wouter
authors: W
authors: Nijkamp
authors: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: Lodewyk F A
authors: LF
authors: Wessels
authors: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: Roderick L
authors: RL
authors: Beijersbergen
authors: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: Rene
authors: R
authors: Bernards
authors: Department of Biochemistry, The Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, QC H3G 1Y6, Canada.
authors: Sidong
authors: S
authors: Huang
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D063150:Polycomb Repressive Complex 1 / Q000096:biosynthesis; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics; D011799:Quinazolines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C570479:CBX2 protein, human; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D011799:Quinazolines; C504738:SMARCE1 protein, human; D063150:Polycomb Repressive Complex 1; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D000077156:Gefitinib
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