Targeting the Spliceosome as a Novel Treatment for Non-Small Cell Lung Cancer

The spliceosome plays an important role in mRNA processing and gene expression regulation, and any faults or dysregulation in the mRNA splicing process can lead to the generation of altered mRNA variants and abnormal proteins, potentially contributing to the production of cancer-specific mRNAs or proteins that drive oncogenic processes. This thesis focuses on exploring the dysregulation of the spliceosome in non-small cell lung carcinoma (NSCLC), as well as the application of spliceosome Sm proteins targeting in NSCLC in vitro and in vivo preclinical models. Following a comprehensive overview of the knowledge of the spliceosome in the context of the macromolecular mRNA processing machinery, the regulation of its activity in mRNA processing and its dysregulation in lung cancer, the thesis discusses current spliceosome targeting strategies in cancer treatment, emphasizing that targeting the spliceosome in lung cancer is an emerging research area. Next, combined with our knowledge of the physical assembly of spliceosome Sm proteins complex, we design a methodology to establish a reporter platform for quantifying the protein-protein interaction (PPI) between two adjacent spliceosome Sm proteins in the Sm ring, i.e., SmD1 and SmD2, in living NSCLC cells, which empower the screening and functional validation of candidates targeting the SmD1 SmD2 PPI in preclinical research in the future. We then optimize NSCLC-CAM tumor models either in ovo or ex ovo with the goal of minimizing animal experiments, as any preclinical evaluation of novel anticancer treatments will eventually include in vivo. This technology holds promise for subsequent research on cancer biology and potential therapeutic targets. Additionally, by focusing on SmD2, the thesis evaluates the potential application of targeting Sm genes in multiple cancers and correlates the Sm genes expression and sensitivity to several FDA-approved anticancer drugs by utilizing in vitro and in silico analysis. In conclusion, this thesis provides new insights into the potential utility of targeting Sm proteins to treat cancer.