Pancreatic ductal adenocarcinoma(PDAC)is currently one of the most lethal cancers worldwide.Several basic studies have confirmed that Kirsten rat sarcoma virus(KRAS)is a key driver gene for the occurrence of PDAC,and KRAS mutations have also been found in most patients in clinical studies.In this study,two pan-KRAS inhibitors,BI-2852 and BAY-293,were chosen as chemical probes to investigate their antitumor potency in PDAC.Their inhibitory effects on KRAS activation were validated in vitro and their antiproliferative potency in PDAC cell lines were profiled,with half-maximal inhibitory concentration(IC50)values of approximately 1 μM,demonstrating the therapeutic potential of pan-KRAS inhibitors in the treatment of PDAC.However,feedback regulation in the KRAS pathway weakened inhibitor activity,which was observed by a 50 times difference in BAY-293 from in vitro activity.Furthermore,pan-KRAS inhibitors effectively inhibited cell proliferation in 3D organoids cultured from PDAC patient samples;however,there were some variations between individuals.These results provide a sufficient theoretical foundation for KRAS as a clinical therapeutic target and for the application of pan-KRAS inhibitors in the treatment of PDAC,with important scientific significance in translational medicine.

Cheng-xiang Wang;Ting-ting Wang;Kun-dong Zhang;Ming-yu Li;Qian-cheng Shen;Shao-yong Lu;Jian Zhang

State Key Laboratory of Oncogenes and Related Genes,Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education,Shanghai Jiao Tong University,School of Medicine,Shanghai 200025,China;Medicinal Chemistry and Bioinformatics Center,Shanghai Jiao Tong University,School of Medicine,Shanghai 200025,China;Department of General Surgery,Shanghai General Hospital,Shanghai Jiao Tong University,Shanghai 200080,China;School of Pharmaceutical Sciences,Zhengzhou University,Zhengzhou 450001,China

中国药理学报（英文版）

[1]Cheng-xiang Wang;Ting-ting Wang;Kun-dong Zhang;Ming-yu Li;Qian-cheng Shen;Shao-yong Lu;Jian Zhang-.Pan-KRAS inhibitors suppress proliferation through feedback regulation in pancreatic ductal adenocarcinoma)[J].中国药理学报（英文版）,2022(10):2696-2708

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