Pharmacologic decoupling of IRBC activation from anabolic collapse redefines ribosome biogenesis inhibition as a selective tumor suppressive strategy

Abstract

Ribosome biogenesis (Ri-Bi) is widely targeted in cancer therapy, yet its inhibition is generally viewed as a broadly anti-anabolic intervention. In colorectal cancer, frontline treatments such as FOLFOX partly disrupt Ri-Bi, eliciting two biologically distinct outputs: an early p53-dependent checkpoint activation, known as the impaired ribosome biogenesis checkpoint (IRBC), and a later global anti-anabolic collapse associated with toxicity and limited durability. At clinically relevant doses, these outputs have been considered pharmacologically inseparable. Here we demonstrate that Ri-Bi inhibition can be functionally dissociated and selectively tuned toward checkpoint engagement. Using a genome-engineered Venus-RPL11 reporter and TP53 isogenic colorectal cancer models, we show that combining sub-effective doses of mechanistically distinct Ri-Bi inhibitors reprograms the cellular response toward dominant IRBC-mediated p53 activation while minimizing p53-independent cytotoxicity. This dose architecture induces profound growth suppression exclusively in TP53-proficient cells and prevents adaptive outgrowth during prolonged treatment. Importantly, pharmacologic rescue of mutant p53 (R175H) with arsenic trioxide restores IRBC responsiveness, extending this framework to genetically advanced disease. Together, our findings establish that ribosome biogenesis inhibition can be selectively directed toward nucleolar surveillance activation, redefining Ri-Bi targeting as a checkpoint-based therapeutic principle.