Small molecule RNA therapeutics to target prostate cancer [Ribo-seq]
Tuning protein expression by targeting RNA structure using small molecules is an unexplored avenue for cancer treatment. To understand whether this vulnerability could be therapeutically targeted in the most lethal form of prostate cancer, castrate-resistant prostate cancer (CRPC), we used a clinical small molecule, zotatifin, that targets the RNA helicase and translation factor eIF4A. Zotatifin repressed tumorigenesis in patient-derived and xenograft models and prolonged survival in vivo alongside hormone therapy. Genome-wide transcriptome, translatome, and proteomic analysis revealed two important translational targets: Androgen Receptor (AR), a key oncogene in CRPC, and hypoxia-inducible factor 1A (HIF1A), an essential cancer modulator in hypoxia. We solved the structure of the 5'UTRs of these oncogenic mRNAs and strikingly observed complex structural remodeling of these select mRNAs by this small molecule. Remarkably, tumors treated with zotatifin become more sensitive to radiotherapy, usually blunted by HIF1A. Therefore, 'translatome therapy' opens new avenues to treat the deadliest cancers. Overall design: Translational landscape of 22Rv1 cell xenografts upon eIF4A inhibitor zotatifin were analyzed by performing Riboseq. Three independent replicates are used for each sample.