Evaluation of cell death pathways by lifirafenib application to pancreas cancer cells

Pancreatic ductal adenocarcinoma (PDAC) is a metastatic cancer type associated with poor prognosis. The development of PDAC is linked to somatic mutations in oncogenes and tumor suppressor genes. Notably, mutations in the Kirsten RAS gene (KRAS) are observed in approximately 95% of pancreatic cancer patients. This study focuses on lifirafenib, one of the inhibitors currently undergoing clinical trials that has been developed to suppress oncogenes such as the epidermal growth factor receptor (EGFR) and KRAS. Moreover, lifirafenib is associated with resistance to cancer therapies under conditions such as apoptosis, acidosis, and hypoxia. Therefore, investigating molecular targets related to the hypoxia-induced tumor microenvironment is of great importance. Carbonic anhydrase9 (KA9) is a cell surface glycoprotein involved in the adaptations to hypoxia and acidosis, playing a role in cancer progression. In this study, the aim was to investigate the effects of lifirafenib on Panc02 cells by evaluating gene expression related to alkaliptosis and apoptosis, and to understand its molecular mechanism for potential use as a therapeutic agent in pancreatic cancer. qRT-PCR and immunocytochemistry methods were employed to detect markers of apoptosis and alkaliptosis. Lifirafenib, applied at different doses, reduced cell viability of Panc02 cells by more than 50%. While quantitative real-time polymerase chain reaction (qRT-PCR) results showed a decrease in the expression of all apoptotic markers, an increase in protein levels was observed compared to the control group. In conclusion, we can say that lifirafenib induces programmed and unprogrammed death in Panc02 cells and activates different death pathways at the protein level. These findings suggest that targeted therapeutic approaches hold promise in the management of pancreatic cancer.