Abstract
The occurrence of inactivating mutations in SWI/SNF chromatin-remodeling genes in common cancers has attracted a great deal of interest. However, mechanistic strategies to target tumor cells carrying such mutations are yet to be developed. This study proposes a synthetic-lethality therapy for treating cancers deficient in the SWI/SNF catalytic (ATPase) subunit, BRG1/SMARCA4. The strategy relies upon inhibition of BRM/SMARCA2, another catalytic SWI/SNF subunit with a BRG1-related activity. Immunohistochemical analysis of a cohort of non-small-cell lung carcinomas (NSCLC) indicated that 15.5% (16 of 103) of the cohort, corresponding to preferentially undifferentiated tumors, was deficient in BRG1 expression. All BRG1-deficient cases were negative for alterations in known therapeutic target genes, for example, EGFR and DDR2 gene mutations, ALK gene fusions, or FGFR1 gene amplifications. RNA interference (RNAi)-mediated silencing of BRM suppressed the growth of BRG1-deficient cancer cells relative to BRG1-proficient cancer cells, inducing senescence via activation of p21/CDKN1A. This growth suppression was reversed by transduction of wild-type but not ATPase-deficient BRG1. In support of these in vitro results, a conditional RNAi study conducted in vivo revealed that BRM depletion suppressed the growth of BRG1-deficient tumor xenografts. Our results offer a rationale to develop BRM-ATPase inhibitors as a strategy to treat BRG1/SMARCA4-deficient cancers, including NSCLCs that lack mutations in presently known therapeutic target genes.
©2013 AACR.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / pathology
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Adenocarcinoma / therapy
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Adult
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Aged
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Aged, 80 and over
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Anaplastic Lymphoma Kinase
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Animals
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Apoptosis*
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Blotting, Western
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Carcinoma, Non-Small-Cell Lung / genetics*
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Carcinoma, Non-Small-Cell Lung / pathology
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Carcinoma, Non-Small-Cell Lung / therapy
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / pathology
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Carcinoma, Squamous Cell / therapy
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Cell Cycle
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Cell Differentiation
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Cell Proliferation
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Cellular Senescence
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DNA Helicases / antagonists & inhibitors
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DNA Helicases / genetics*
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DNA Helicases / metabolism
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Discoidin Domain Receptors
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Female
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Fluorescent Antibody Technique
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Genes, Lethal
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Humans
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Immunoenzyme Techniques
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Kinesins / genetics
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Lung Neoplasms / genetics
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Lung Neoplasms / pathology
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Lung Neoplasms / therapy
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Microscopy, Fluorescence
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Middle Aged
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Mutation / genetics
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Neoplasm Staging
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Oncogene Proteins, Fusion / genetics
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RNA, Small Interfering / genetics*
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Receptor Protein-Tyrosine Kinases / genetics
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Receptors, Mitogen / genetics
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics*
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Transcription Factors / metabolism
Substances
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EML4-ALK fusion protein, human
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KIF5B protein, human
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KIF5B-RET fusion protein, human
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Nuclear Proteins
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Oncogene Proteins, Fusion
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RNA, Small Interfering
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Receptors, Mitogen
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SMARCA2 protein, human
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Transcription Factors
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ALK protein, human
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Alk protein, mouse
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Anaplastic Lymphoma Kinase
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Discoidin Domain Receptors
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Receptor Protein-Tyrosine Kinases
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SMARCA4 protein, human
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DNA Helicases
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Kinesins