Small-molecule RNA therapeutics to target prostate cancer

Abstract

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, castration-resistant prostate cancer (CRPC), we use a clinical small molecule, zotatifin, that targets the RNA helicase and translation factor eukaryotic initiation factor 4A (eIF4A). Zotatifin represses tumorigenesis in patient-derived and xenograft models and prolonged survival in vivo alongside hormone therapy. Genome-wide transcriptome, translatome, and proteomic analysis reveals 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 solve the structure of the 5′ UTRs of these oncogenic mRNAs and strikingly observe complex structural remodeling of these select mRNAs by this small molecule. Remarkably, tumors treated with zotatifin become more sensitive to anti-androgen therapy and radiotherapy. Therefore, “translatome therapy” provides additional strategies to treat the deadliest cancers.