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

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

Molecular Cancer Research

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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.

Original language	English
Pages (from-to)	445-458
Number of pages	14
Journal	Cell Research
Volume	25
Issue number	4
DOIs	https://doi.org/10.1038/cr.2015.16
Publication status	Published - Apr 2015

Keywords

Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms
Mutation
Polycomb Repressive Complex 1
Proto-Oncogene Proteins c-met
Quinazolines
Receptor Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor
Signal Transduction
EGFR signaling
drug resistance
RNAi screening

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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.",

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author = "Papadakis, {Andreas I} and Chong Sun and Knijnenburg, {Theo A} and Yibo Xue and Wipawadee Grernrum and Michael H{\"o}lzel and Wouter Nijkamp and Wessels, {Lodewyk F A} and Beijersbergen, {Roderick L} and Rene Bernards and Sidong Huang",

year = "2015",

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doi = "10.1038/cr.2015.16",

language = "English",

volume = "25",

pages = "445--458",

journal = "Cell Research",

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AU - Papadakis, Andreas I

AU - Sun, Chong

AU - Knijnenburg, Theo A

AU - Xue, Yibo

AU - Grernrum, Wipawadee

AU - Hölzel, Michael

AU - Nijkamp, Wouter

AU - Wessels, Lodewyk F A

AU - Beijersbergen, Roderick L

AU - Bernards, Rene

AU - Huang, Sidong

PY - 2015/4

Y1 - 2015/4

N2 - 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.

AB - 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.

KW - Carcinoma, Non-Small-Cell Lung

KW - Cell Line, Tumor

KW - Chromosomal Proteins, Non-Histone

KW - DNA-Binding Proteins

KW - Drug Resistance, Neoplasm

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Lung Neoplasms

KW - Mutation

KW - Polycomb Repressive Complex 1

KW - Proto-Oncogene Proteins c-met

KW - Quinazolines

KW - Receptor Protein-Tyrosine Kinases

KW - Receptor, Epidermal Growth Factor

KW - Signal Transduction

KW - EGFR signaling

KW - drug resistance

KW - RNAi screening

U2 - 10.1038/cr.2015.16

DO - 10.1038/cr.2015.16

M3 - Article

C2 - 25656847

SN - 1001-0602

VL - 25

SP - 445

EP - 458

JO - Cell Research

JF - Cell Research

IS - 4

ER -

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

Abstract

Keywords

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