Machine learning uncovers CEP55 as a target for overcoming sorafenib resistance in hepatocellular carcinoma

Background: Drug resistance, especially to sorafenib, the primary systemic treatment for advanced-stage hepatocellular carcinoma (HCC), critically affects the management of HCC. Objectives: This study aimed to identify key genetic biomarkers that could predict treatment outcomes and serve as potential targets for personalized therapy. Methods: This was a retrospective, bioinformatics-based study integrating RNA sequencing data from public databases. Utilizing high-throughput genomic technologies and machine learning approaches, RNA sequencing data from The Cancer Genome Atlas were integrated with pharmacogenetic profiles. LASSO regression was employed to analyze these data sets, leading to the identification of centrosomal protein 55 (CEP55) as a significant biomarker. CRISPR-based pharmacogenetic analysis was then performed to further explore the therapeutic potential of targeting this gene alongside glutathione treatment. Results: Through integrated bioinformatics analysis, 40 genes were found to be associated with sorafenib resistance in HCC. LASSO-Cox regression analysis revealed CEP55 as the most significant predictor of patient survival, with high CEP55 expression being strongly correlated with poor overall survival from HCC. Although HCC cells with elevated CEP55 expression demonstrated significant sorafenib resistance, CEP55 -knockout effectively sensitized cells to glutathione treatment, highlighting the potential of targeting CEP55 alongside glutathione as an effective strategy for overcoming sorafenib resistance in HCC. Conclusion: This integrated approach highlights the efficacy of machine learning in identifying novel biomarkers and therapeutic targets. Our study underscores the importance of CEP55 as a key mediator in sorafenib resistance, laying the foundation for personalized treatment strategies. However, further laboratory and clinical validation of CEP55 inhibition combined with glutathione therapy are needed to transform HCC management and tackle challenges related to drug resistance.