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 cotreatment is driven by translational rewiring that results in dysregulated cellular metabolism and induction of a cAMP-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.

• Authors: Eric P Kusnadi, Anna S Trigos, Carleen Cullinane, David L Goode, Ola Larsson, Jennifer R Devlin, Keefe T Chan, David P De Souza, Malcolm J McConville, Grant A McArthur, George Thomas, Elaine Sanij, Gretchen Poortinga, Ross D Hannan, Katherine M Hannan, Jian Kang, Richard B Pearson
• Journal: The EMBO journal (EMBO J) Vol. 39 Issue 21 Pg. e105111 (11 02 2020) ISSN: 1460-2075 [Electronic] England
• PMID: 32945574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Chemical References

• Antineoplastic Agents
• Benzothiazoles
• CX 5461
• Guanine Nucleotide Exchange Factors
• Naphthyridines
• Protein Kinase Inhibitors
• RAPGEF3 protein, human
• RAPGEF4 protein, human
• RNA, Messenger
• RNA, Ribosomal
• Mechanistic Target of Rapamycin Complex 1
• RNA Polymerase I

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Benzothiazoles (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Guanine Nucleotide Exchange Factors (metabolism)
• Humans
• Male
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Mice
• Mice, Inbred C57BL
• Naphthyridines (pharmacology)
• Neoplasms (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Biosynthesis (drug effects, genetics, physiology)
• Protein Kinase Inhibitors
• RNA Polymerase I (metabolism)
• RNA, Messenger (metabolism)
• RNA, Ribosomal
• Ribosomes (drug effects, metabolism)
• Transcription, Genetic (drug effects)
• Transcriptome