Identification and Validation of Alkaliptosis Resistance-Associated Genes in Prostate Cancer Via Transcriptome Sequencing and Prediction of Biochemical Recurrence

Androgen deprivation therapy (ADT) is the primary treatment strategy for prostate cancer. However, despite an initially favorable response, tumors inevitably progress to castration-resistant prostate cancer (CRPC). Therefore, the exploration of new therapeutic approaches targeting CRPC has become imperative. Increasing evidence suggests that hypoxia plays a crucial role in the development of CRPC. In this study, we found that the emergence of alkaliptosis resistance and the expression of its marker, CA9, significantly contribute to the progression of castration resistance induced by hypoxia. This study utilized bioinformatics approaches to identify genetic determinants associated with alkaliptosis resistance and explored the clinical significance of these marker genes. Transcriptomic sequencing was performed on the DU145 prostate cancer cell line, which had been induced to acquire alkaliptosis resistance. Using least absolute shrinkage and selection operator (LASSO) regression analysis, a prognostic risk model consisting of 12 genes, including ADORA2A, KCNG4, SEC14L5, B3GAT2, SLFNL1, FAM72D, CBWD3, PPM1K, STARD4, DEPDC1B, MATN3, and DDIAS was developed. The risk model score demonstrated a strong correlation with key patient clinical characteristics, including Gleason score, PSA levels, T stage, and N stage, and was also associated with immune therapy response and biochemical recurrence-free survival (BCRFS). Furthermore, ADORA2A expression in cellular models was found to be a critical factor in promoting alkaliptosis resistance.