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.
Highlights
Tyrosine kinase inhibitors are effective against solid tumors with activating mutations in tyrosine kinase genes, for example, the EGFR mutations and ALK fusions harbored by lung adenocarcinomas [1]
Two other tyrosine kinase gene alterations, the FGFR1 amplification and the DDR2 mutation, have been identified as therapeutic targets in squamous cell carcinoma, which corresponds to another major type of non–small-cell lung carcino
To address the potential significance of BRM-inhibitory therapies, we examined the characteristics of BRG1-deficient non–smallcell lung carcinomas (NSCLC), including the mutually exclusive relationship between BRG1 deficiencies and mutations in therapeutic target genes (EGFR and DDR2 mutations, ALK fusions, and FGFR1 amplifications; Fig. 1A)
Summary
Tyrosine kinase inhibitors are effective against solid tumors with activating mutations in tyrosine kinase genes, for example, the EGFR mutations and ALK fusions harbored by lung adenocarcinomas [1]. Inactivating somatic mutations of genes that encode subunits of the SWI/SNF chromatinremodeling complex, such as BRG1/SMARCA4, PBRM1/ BAF180, ARID1A/BAF250A, and ARID2/BAF200, have attracted much interest as they were first identified by genome-wide sequencing analyses of cancer cells [7]. Such mutations are thought to interfere with the functions of the SWI/SNF complex in transcription [7] and DNA double-strand break repair [8], which are likely to be critical for cancer development and/ or progression. No therapeutic strategies have yet been developed for targeting cancer cells harboring these inactivating SWI/SNF mutations
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