Exploiting rDNA loci vulnerabilities to treat incurable cancers driven by chromatin mutations

Cancers driven by mutations in genes encoding chromatin modifiers such as sarcomas, and brain cancers are associated with poor prognoses and remain largely untreatable with current therapies. Our preliminary data, focusing on ATRX/H3.3 mutant cancers, reveal that dysregulation of ribosomal DNA (rDNA) genes, critical regions encoding ribosomal RNA, are targetable loci across diverse cancers that are driven by mutation in chromatin modifiers. Notably, this rDNA dysregulation creates a cancer-specific vulnerability in ATRX/H3.3 mutant cancers as our preliminary data demonstrate that such cancers exhibit heightened sensitivity to RNA Polymerase I inhibitors — including CX-5461 and PMR-116, compounds. This work supports a compelling therapeutic rationale and mechanistic insights into how alteration of rDNA loci and nucleolar function drive cancer development and progression.