Pan-KRAS Inhibitors Suppress Proliferation Through Feedback Regulation in Pancreatic Ductal Adenocarcinoma

Overview

Journal Acta Pharmacol Sin

Specialty Pharmacology

Date 2022 Mar 30

PMID 35352018

Authors

Cheng-Xiang Wang

Ting-Ting Wang

Kun-Dong Zhang

Ming-Yu Li

Qian-Cheng Shen

Shao-Yong Lu

Jian Zhang

Affiliations

Soon will be listed here.

Abstract

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 (IC) 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.

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