RNA polymerase I inhibition : mechanism and exploitation in cancer treatment

Sammanfattning: Cancer is an umbrella term for diseases characterized by uncontrollably proliferating abnormal cells that often have also gained the ability to spread and invade other tissues. It is one of the leading causes of death worldwide and the second-leading cause of death in Sweden. Chemotherapy is a commonly used treatment approach, where the drugs preferentially target cellular processes needed for cancer cell proliferation, leading to cancer cell growth arrest or death. Albeit a potent tool in managing cancer, the overall success rate remains low for certain cancer types, highlighting the need to identify new chemotherapeutic targets and strategies. Ribosome biogenesis (RiBi), a fundamental process that supplies cells with ribosomes, represents an emerging target, with several cancer types relying on high RiBi rates to maintain high proliferation rates. Small-molecule-mediated RiBi inhibition induces nucleolar stress, a cellular response resulting in cell cycle arrest, and apoptosis, often dependent on p53. Pre-clinical studies have shown promising results in a variety of cancer types; however, the compounds available are limited, and their mechanistic details are yet to be explored. Thus, the characterization of cancer-specific biological effects of RiBi inhibition, together with the identification of new RiBi targets and inhibitors, may expand the therapeutic promise of this strategy, accelerate the clinical development of drug candidates and potentially facilitate the selection of patients who might benefit from the clinical use of RiBi inhibitors in the future. The primary aim of the Thesis was to study: 1. the pharmacological inhibition of RiBi focusing on RNA polymerase I (Pol I), and repurposing of clinically approved drugs with underappreciated RiBi-inhibitory effects for cancer treatment 2. the effects of Pol I inhibition in high-grade gliomas (HGG) and identify synergistic treatment strategies to prevent potential resistance development 3. alternative druggable RiBi-associated protein targets In Paper I, we identified an FDA-approved antimalarial drug, amodiaquine, with previously unknown Pol I inhibitory effects. We designed and synthesized a chemical analog with comparable efficacy to limit potential toxicity and demonstrated the effectiveness of the analog series in a panel of colorectal cancer cell lines. In Paper II, we reported the relevance and effectiveness of RiBi as a target in HGG, uncovered a novel cellular response to nucleolar stress, mediated by the Fibroblast Growth Factor 2 (FGF2)- Fibroblast Growth factor receptor 1 (FGFR1) signaling axis, and proposed a highly synergistic combination with FGFR inhibitors to limit glioma cell growth. In Paper III, we further characterized the functional role of the DEAD-Box Helicase and Exon Junction Complex protein, eIF4A3, and suggested its relevance as a target for drug discovery, showing its involvement in RiBi and highlighting its association with tumor aggressiveness.