Pan-KRAS inhibitors suppress proliferation through feedback regulation in pancreatic ductal adenocarcinoma
Cheng-Xiang Wang , Ting-Ting Wang, Kun-Dong Zhang , Ming-Yu Li , Qian-Cheng Shen , Shao-Yong Lu, Jian Zhang
Pancreatic ductal adenocarcinoma (PDAC) is presently probably the most lethal cancers worldwide. Several fundamental research has confirmed that Kirsten rat sarcoma virus (KRAS) is really a key driver gene for the appearance of PDAC, and KRAS mutations are also present in most sufferers in studies. Within this study, two pan-KRAS inhibitors, BI-2852 and BAY-293, were selected as chemical probes to research their antitumor potency in PDAC. Their inhibitory effects on KRAS activation were validated in vitro as well as their antiproliferative potency in PDAC cell lines were profiled, with half-maximal inhibitory concentration (IC50) values of roughly 1 |¨¬M, demonstrating the therapeutic potential of pan-KRAS inhibitors in treating PDAC. However, feedback regulation within the KRAS path weakened inhibitor activity, that was observed with a 50 occasions improvement in BAY-293 from in vitro activity. In addition, pan-KRAS inhibitors effectively inhibited cell proliferation in 3D organoids cultured from PDAC patient samples however, there have been some variations between individuals. These results give a sufficient theoretical foundation for KRAS like a clinical therapeutic target but for the use of pan-KRAS inhibitors in treating PDAC, significant scientific significance in translational medicine.