Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis

Abstract

Elevated ribosome biogenesis in oncogene-driven cancers is commonly targeted byDNA-damaging cytotoxic drugs. Our previous first-in-human trial ofCX-5461, a novel, less genotoxic agent that specifically inhibits ribosome biogenesis via suppression ofRNApolymerase I (Pol I) transcription, revealed single-agent efficacy in refractory blood cancers. Despite this clinical response, patients were not cured. In parallel, we demonstrated a marked improvement in thein vivoefficacy ofCX-5461 in combination withPI3K/AKT/mTORC1 pathway inhibitors. Here, we reveal the molecular basis for this improved efficacy observedin vivo, which is associated with specific suppression of translation ofmRNAs encoding regulators of cellular metabolism. Importantly, acquired resistance to this cotreatment is driven by translational rewiring that results in dysregulated cellular metabolism and induction of acAMP-dependent pathway critical for the survival of blood cancers including lymphoma and acute myeloid leukemia. Our studies thus identify key molecular mechanisms underpinning the response of blood cancers to selective inhibition of ribosome biogenesis and define metabolic vulnerabilities that will facilitate the rational design of more effective regimens for Pol I-directed therapies.