Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2021.145
Combination Therapy of the Active KRAS-Targeting Antibody inRas37 and a PI3K Inhibitor in Pancreatic Cancer
Ji Eun Lee1,†, Min Gyu Woo1,†, Kyung Hee Jung1,†, Yeo Wool Kang1, Seung-Min Shin2, Mi Kwon Son1, Zhenghuan Fang1, Hong Hua Yan1, Jung Hee Park1, Young-Chan Yoon1, Yong-Sung Kim2 and Soon-Sun Hong1,*
1Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University, Incheon 22332, 2Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea
*E-mail: hongs@inha.ac.kr
Tel: +82-32-890-3683, Fax: +82-32-890-2462
The first three authors contributed equally to this work.
Received: September 7, 2021; Revised: September 16, 2021; Accepted: September 23, 2021; Published online: October 19, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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: Pancreatic cancer, KRAS, Targeting antibody, PI3K, BEZ-235


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