Dysregulated Ribosome Biogenesis Reveals Therapeutic Liabilities in Cancer

Causal associations between hereditary and acquired dysregulation of ribosome biogenesis (RiBi) and an increased risk of cancer have been established. However, the mechanisms underlying these associations are only beginning to be explored. Various types of RiBi dysregulation have been linked with alterations in protein synthesis and proteostasis, metabolic processes, redox homeostasis, genome stability, and transcription. Understanding how these alterations contribute to cancer pathogenesis is of great interest as it may reveal targetable cancer vulnerabilities. Impairment of RiBi redirects the nascent preribosomal RNA complex containing ribosomal protein L5 (RPL5), RPL11, and 5S rRNA from RiBi to bind the human homolog of mouse double minute 2 (HDM2) and thereby block HDM2-mediated ubiquitination and degradation of the tumor suppressor p53. This signaling pathway was recently named the impaired ribosome biogenesis checkpoint (IRBC). Animal studies suggest that IRBC signaling acts as a barrier to tumorigenesis by triggering apoptosis or senescence and by preventing DNA damage and genome instability. Recent evidence for the positive selection of specific RPL5 and RPL11 gene mutations in human tumors with wt TP53 further strengthens the role this pathway plays in tumor suppression. CX-5461, the first direct and selective inhibitor of RNA polymerase I, limits tumorigenesis by activating the IRBC. By inhibiting rDNA transcription, CX-5461 triggers rDNA replication stress, thereby explaining synthetic lethal interactions in cancers harboring genetic defects in homologous recombination (HR) or nonhomologous end joining (NHEJ) DNA repair pathways. Ribosome biogenesis (RiBi) is one of the most complex and energy demanding processes in human cells, critical for cell growth and proliferation. Strong causal links between inherited and acquired impairment in RiBi with cancer pathogenesis are emerging, pointing to RiBi as an attractive therapeutic target for cancer. Here, we will highlight new knowledge about causes of excessive or impaired RiBi and the impact of these changes on protein synthesis. We will also discuss how new knowledge about secondary consequences of dysregulated RiBi and protein synthesis, including proteotoxic stress, metabolic alterations, adaptive transcriptional and translational programs, and the impaired ribosome biogenesis checkpoint (IRBC) provide a foundation for the development of new anticancer therapies. Ribosome biogenesis (RiBi) is one of the most complex and energy demanding processes in human cells, critical for cell growth and proliferation. Strong causal links between inherited and acquired impairment in RiBi with cancer pathogenesis are emerging, pointing to RiBi as an attractive therapeutic target for cancer. Here, we will highlight new knowledge about causes of excessive or impaired RiBi and the impact of these changes on protein synthesis. We will also discuss how new knowledge about secondary consequences of dysregulated RiBi and protein synthesis, including proteotoxic stress, metabolic alterations, adaptive transcriptional and translational programs, and the impaired ribosome biogenesis checkpoint (IRBC) provide a foundation for the development of new anticancer therapies.