Re: Ashley M. Hopkins, Ganessan Kichenadasse, Christos S. Karapetis, et al. Concomitant Proton Pump Inhibitor Use and Survival in Urothelial Carcinoma Treated with Atezolizumab. Clin Cancer Res. In press. https://doi.org/10.1158/1078-0432.CCR-20-1876

Vollständiger Abstract

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PURPOSE: Rhabdoid tumors (RTs) are highly aggressive pediatric cancers driven by the biallelic inactivation of the SMARCB1 tumor suppressor gene, the sole recurrent genetic alteration. SMARCB1 encodes a core subunit of the SWI/SNF chromatin remodeling complex; its loss disrupts epigenetic gene regulation, supporting the classification of RTs as prototypical epigenetically driven cancers and highlighting the therapeutic potential of targeting epigenetic modifiers. Notably, previous studies have reported the overexpression of DNMT3A and DNMT3B, enzymes responsible for de novo DNA methylation, in RTs. EXPERIMENTAL DESIGN: Using patient samples, cell lines, and an ex vivo brain organoid system, combined with immunohistochemistry and bioinformatics, we investigated the role of DNMT3 enzymes in RT progression. RESULTS: In a composite tumor case, SMARCB1-deficient and -proficient regions displayed distinct methylation profiles. SMARCB1 loss correlated with increased DNA methylation and DNMT3A/B overexpression. To assess their respective roles in RTs, we used CRISPR-Cas9 to knock out DNMT3A/B in a SMARCB1-inducible RT cell line. DNMT3B loss impaired viability more strongly than DNMT3A. DNMT3B knock-out and SMARCB1 re-expression regulated overlapping gene programs related to development and cell adhesion at methylation and transcriptional levels. We next demonstrated that the cytotoxicity of the DNMT inhibitor decitabine, which impairs RT cell growth in human iPS-derived cerebral organoids, is primarily mediated by DNMT3B. CONCLUSIONS: These results show that DNMT3B plays a key role in the cascade of epigenetic effects following SMARCB1 loss and is pivotal in the RT sensitivity to decitabine; our study therefore supports the development of DNMT3B-specific inhibitors for RT.

Abstract: PubMed · Datensatz