title: A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1.
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.
authors.affiliation: Divisions of Genome Biology and Multistep Carcinogenesis, National Cancer Center Research Institute, Tokyo, Japan, USA.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oike
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ogiwara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tominaga
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ito
authors.forename: Osamu
authors.initials: O
authors.lastname: Ando
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuta
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Mizukami
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shimada
authors.forename: Hisanori
authors.initials: H
authors.lastname: Isomura
authors.forename: Mayumi
authors.initials: M
authors.lastname: Komachi
authors.forename: Koh
authors.initials: K
authors.lastname: Furuta
authors.forename: Shun-Ichi
authors.initials: S
authors.lastname: Watanabe
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000628:therapy; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D016922:Cellular Senescence; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000070818:Discoidin Domain Receptors; D005260:Female; D005455:Fluorescent Antibody Technique; D005804:Genes, Lethal; D006801:Humans; D007124:Immunoenzyme Techniques; D016547:Kinesins / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D011975:Receptors, Mitogen / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C522504:EML4-ALK fusion protein, human; C488101:KIF5B protein, human; C573239:KIF5B-RET fusion protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D011975:Receptors, Mitogen; C084011:SMARCA2 protein, human; D014157:Transcription Factors; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D016547:Kinesins