Fibrillarin-mediated ribosomal RNA maturation is a novel therapeutic vulnerability in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) remains one of the most challenging breast cancer subtypes to treat due to the lack of effective therapeutic options. Ribosome biogenesis has recently emerged as a promising therapeutic target across various cancers. Despite the current targeting of ribosome biogenesis through RNA polymerase I (RNA Pol I) inhibition, we speculated that other factors essential for ribosome assembly, such as rRNA maturation factors, may also represent therapeutic targets in TNBC. Here, we demonstrate that ribosome biogenesis-related genes are notably overexpressed in TNBC compared to other breast cancer subtypes, highlighting its critical role in TNBC progression. Accordingly, we show that RNA Pol I inhibition exerts potent anti-proliferative effects in pre-clinical models of TNBC, both in vitro and in vivo. However, the DNA-damaging activity of RNA Pol I inhibitors raises safety concerns, highlighting the need for alternative strategies to inhibit ribosome biogenesis. To this end, we show that targeting a downstream rRNA maturation step, specifically pre-rRNA cleavage, by inhibiting the maturation factor Fibrillarin, also inhibits tumor growth in TNBC models. Notably, ribosome biogenesis inhibition, through either RNA Pol I or Fibrillarin targeting, induces cell cycle arrest without triggering significant cell death. These findings establish ribosome biogenesis as a therapeutic vulnerability in TNBC and identify rRNA maturation, and Fibrillarin in particular, as novel targets for potential therapeutic intervention. SignificanceTargeting ribosome biogenesis, through inhibition of either rRNA synthesis or maturation, induces anti-tumoral effects in TNBC, representing a novel therapeutic vulnerability with potential to improve patient outcomes.