American Association for Cancer Research
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Supplementary Tables from A Synthetic Lethality–Based Strategy to Treat Cancers Harboring a Genetic Deficiency in the Chromatin Remodeling Factor BRG1

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journal contribution
posted on 2023-03-30, 21:42 authored by Takahiro Oike, Hideaki Ogiwara, Yuichi Tominaga, Kentaro Ito, Osamu Ando, Koji Tsuta, Tatsuji Mizukami, Yoko Shimada, Hisanori Isomura, Mayumi Komachi, Koh Furuta, Shun-Ichi Watanabe, Takashi Nakano, Jun Yokota, Takashi Kohno

PDF file, 106K, Supplementary Table S1. BRG1-deficient and -proficient cell lines subjected to BRM knockdown Supplementary Table S2. Verification of gene alterations in cell lines subjected to BRM knockdown Supplementary Table S3. Analysis of missense BRG1 mutations using the Polyphen software Supplementary Table S4. Negative correlation between BRG1 deficiency and alterations in therapeutic target genes in 373 NSCLC cases from three studies (this study and Refs 32 and 33) Supplementary Table S5. Correlation between BRG1 deficiency and smoking in 369 NSCLC cases from three studies (this study and Ref 32 and 33).



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. Cancer Res; 73(17); 5508–18. ©2013 AACR.

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