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

Acta Pharmacologica Sinica volume 43, pages 2696–2708 (2022)Cite this article

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 (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.

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Fig. 1: BI-2852 and BAY-293 inhibited the activation of Kirsten rat sarcoma virus (KRAS) mediated by SOS1.
Fig. 2: BAY-293 slightly inhibited proliferation of Kirsten rat sarcoma virus (KRAS)-driven cancer cells in 2D culture.
Fig. 3: BI-2852 and BAY-293 inhibited proliferation of Kirsten rat sarcoma virus (KRAS)-driven cancer cells.
Fig. 4: BAY-293 regulated Kirsten rat sarcoma virus (KRAS) signaling pathway.
Fig. 5: BAY-293 induced feedback regulations in pancreatic ductal adenocarcinoma (PDAC).
Fig. 6: BAY-293 promoted pancreatic ductal adenocarcinoma (PDAC) cell apoptosis.
Fig. 7: Modeling human pancreatic ductal adenocarcinoma (PDAC) with patient-derived organoids.
Fig. 8: BAY-293 inhibited cell growth of pancreatic ductal adenocarcinoma (PDAC) patient-derived organoids.

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Acknowledgements

This work was partly supported by grants from the National Natural Science Foundation of China (81925034, 22077082, 91753117, and 81721004), Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-01-E00036, China), Shanghai Science and Technology Innovation (19431901600, China), Shanghai Health and Family Planning System Excellent Subject Leader and Excellent Young Medical Talents Training Program (2018BR12, China), CAMS Innovation Fund for Medical Sciences (CIFMS) (2019-I2M-5-051), and Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases.

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  1. These authors contributed equally: Cheng-xiang Wang, Ting-ting Wang and Kun-dong Zhang

Authors and Affiliations

  1. 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

    Cheng-xiang Wang, Ming-yu Li, Shao-yong Lu & Jian Zhang

  2. Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China

    Ting-ting Wang, Qian-cheng Shen, Shao-yong Lu & Jian Zhang

  3. Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China

    Kun-dong Zhang

  4. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China

    Jian Zhang

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  1. Cheng-xiang Wang
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Contributions

SYL and JZ conceived and designed the experiments; CXW and TTW performed the experiments and analyzed the data; KDZ provided patient samples for PDO culture; MYL and QCS visualized the data; SYL and JZ contributed reagents, materials, and analytical tools. CXW wrote the original manuscript and SYL edited and revised the manuscript. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Shao-yong Lu or Jian Zhang.

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Wang, Cx., Wang, Tt., Zhang, Kd. et al. Pan-KRAS inhibitors suppress proliferation through feedback regulation in pancreatic ductal adenocarcinoma. Acta Pharmacol Sin 43, 2696–2708 (2022). https://doi.org/10.1038/s41401-022-00897-4

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  • DOI: https://doi.org/10.1038/s41401-022-00897-4

Keywords

  • pancreatic ductal adenocarcinoma
  • KRAS
  • driver gene
  • BAY-293
  • organoid

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