Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis

ABSTRACT: Elevated ribosome biogenesis in oncogene-driven cancers is commonly targeted by DNA-damaging cytotoxic drugs. Our previous first-in-human trial of CX-5461, a novel, less genotoxic agent that specifically inhibits ribosome biogenesis via suppression of RNA Polymerase 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 the in vivo efficacy of CX-5461 in combination with PI3K/AKT/mTORC1 pathway inhibitors. Here we reveal the molecular basis for this improved efficacy observed in vivo, which is associated with specific suppression of translation of mRNAs encoding regulators of cellular metabolism. Importantly, acquired resistance to this co-treatment is

SUBMITTER: Dr. Eric, P Kusnadi 

PROVIDER: S-SCDT-EMBOJ-2020-105111 | biostudies-other |

REPOSITORIES: biostudies-other