Pan-KRAS inhibitors suppress proliferation through feedback regulation in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers globally. Extensive research has established that mutations in the Kirsten rat sarcoma virus (KRAS) gene play a pivotal role in the development of PDAC, with such mutations being prevalent in most clinical cases. This study focused on two pan-KRAS inhibitors, BI-2852 and BAY-293, using them as chemical probes to evaluate their antitumor efficacy against PDAC. The inhibitors’ ability to suppress KRAS activation was confirmed in vitro, and their antiproliferative effects were assessed across PDAC cell lines, showing half-maximal inhibitory concentration (IC50) values around 1 μM, indicating their therapeutic promise for PDAC treatment. However, feedback regulation within the KRAS pathway diminished the inhibitors’ effectiveness, as seen by a 50-fold discrepancy in BAY-293‘s in vitro activity. Additionally, pan-KRAS inhibitors significantly inhibited cell proliferation in 3D organoids derived from PDAC patient samples, though responses varied between individuals. These findings underscore the potential of targeting KRAS in clinical therapy and highlight the significance of pan-KRAS inhibitors in advancing PDAC treatment, with notable implications for translational medicine.