Misregulation of translation drives prostate cancer drug resistance

Emerging evidence associates translation factors and regulators to tumorigenesis. Recent advances in our ability to perform global translatome analyses indicate that our understanding of translational changes in cancer resistance is still limited. Here, we characterize global translational changes that occur during the acquisition of prostate cancer (PCa) drug resistance. We generated a patient derived xenograft (PDX) model created from PCa cells to recapitulate key features of resistant PCa progression. From an enzalutamide-sensitive patient derived cell line (VCaP), we generated a castration resistant cell line (VCaPCRPC) and an enzalutamide resistant cell line (VCaPER). We performed Total and polyribosome-bound RNA sequencing and mass spectroscopy from both VCaPCRPC and VCaPER to reveal their respective translatomes. We found that in drug-resistant cells, RNAs associated to ribosomes were enriched for nuclear RNA and DNA binding related biological processes, whereas RNAs that are less associated showed enrichment for processes such as cell membrane and cell-cell junction related biological processes. These results were corroborated by mass spectrometry and suggest that translation is indeed affected during drug resistance. Furthermore, our analysis revealed enrichment of long non-coding RNAs associated to ribosomes, which may suggest aberrant translation or translation of novel peptides that can be considered as new biomarkers. Our findings thus point towards novel therapeutic avenues that may target drug-resistant cells.