Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Combination Therapy of the Active KRAS-Targeting Antibody inRas37 and a PI3K Inhibitor in Pancreatic Cancer

  • Lee, Ji Eun (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University) ;
  • Woo, Min Gyu (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University) ;
  • Jung, Kyung Hee (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University) ;
  • Kang, Yeo Wool (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University) ;
  • Shin, Seung-Min (Department of Molecular Science and Technology, Ajou University) ;
  • Son, Mi Kwon (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University) ;
  • Fang, Zhenghuan (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University) ;
  • Yan, Hong Hua (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University) ;
  • Park, Jung Hee (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University) ;
  • Yoon, Young-Chan (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University) ;
  • Kim, Yong-Sung (Department of Molecular Science and Technology, Ajou University) ;
  • Hong, Soon-Sun (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University)
  • Received : 2021.09.07
  • Accepted : 2021.09.23
  • Published : 2022.05.01
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Abstract

KRAS activating mutations, which are present in more than 90% of pancreatic cancers, drive tumor dependency on the RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Therefore, combined targeting of RAS/MAPK and PI3K/AKT signaling pathways may be required for optimal therapeutic effect in pancreatic cancer. However, the therapeutic efficacy of combined MAPK and PI3K/AKT signaling target inhibitors is unsatisfactory in pancreatic cancer treatment, because it is often accompanied by MAPK pathway reactivation by PI3K/AKT inhibitor. Therefore, we developed an inRas37 antibody, which directly targets the intra-cellularly activated GTP-bound form of oncogenic RAS mutation and investigated its synergistic effect in the presence of the PI3K inhibitor BEZ-235 in pancreatic cancer. In this study, inRas37 remarkably increased the drug response of BEZ-235 to pancreatic cancer cells by inhibiting MAPK reactivation. Moreover, the co-treatment synergistically inhibited cell proliferation, migration, and invasion and exhibited synergistic anticancer activity by inhibiting the MAPK and PI3K pathways. The combined administration of inRas37and BEZ-235 significantly inhibited tumor growth in mouse models. Our results demonstrated that inRas37 synergistically increased the antitumor activity of BEZ-235 by inhibiting MAPK reactivation, suggesting that inRas37 and BEZ-235 co-treatment could be a potential treatment approach for pancreatic cancer patients with KRAS mutations.

Keywords

Acknowledgement

This research was supported by the National Research Foundation (NRF) Grant (2021R1A2B5B03086410, 2021R1A5A2031612, 2019M3E5D1A02069621), Republic of Korea.

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