Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis

Abstract

Elevated ribosome biogenesis in oncogene-driven cancers is commonly targeted by DNAdamaging cytotoxic drugs. Our first-in-man trial of CX-5461, a novel, less genotoxic agent that specifically inhibits ribosome biogenesis via suppression of RNA Polymerase I transcription, revealed single agent efficacy in refractory blood cancers. Here we show that the marked improvement in the in vivo efficacy of CX-5461 in combination with PI3K/AKT/mTORC1 pathway inhibitors is associated with specific suppression of translation of mRNAs encoding regulators of cellular metabolism. Importantly, acquired resistance to this co-treatment is driven by translational re-wiring that results in dysregulated cellular metabolism and a cAMPdependent pathway critical for the survival of blood cancers including lymphoma and acute myeloid leukemia. Our studies identify the molecular mechanisms responsible for the acute regulation of the translational apparatus and its functional adaptation upon selective druginduced pressure, and will facilitate the rational design of more effective regimens for Pol Idirected ribosome targeting therapies.

Arginine-rich C9ORF72 ALS proteins stall ribosomes in a manner distinct from a canonical ribosome-associated quality control substrate

“…Polysome profiling analysis was performed as described in ( 57 ). HEK293T cells transfected with GFP, GFP-poly-K, or GFP-102×PR were incubated with 100 μg/ml of cycloheximide (Sigma-Aldrich # 01810-1G) for 5 min prior to harvest.…”