Combination Therapy of the Active KRAS-Targeting Antibody inRas37 and a PI3K Inhibitor in Pancreatic Cancer
10.4062/biomolther.2021.145
- Author:
Ji Eun LEE
1
;
Min Gyu WOO
;
Kyung Hee JUNG
;
Yeo Wool KANG
;
Seung-Min SHIN
;
Mi Kwon SON
;
Zhenghuan FANG
;
Hong Hua YAN
;
Jung Hee PARK
;
Young-Chan YOON
;
Yong-Sung KIM
;
Soon-Sun HONG
Author Information
1. Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University, Incheon 22332, Republic of Korea
- Publication Type:Original Article
- From:Biomolecules & Therapeutics
2022;30(3):274-283
- CountryRepublic of Korea
- Language:English
-
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.
