한빛사 논문
Seung-Min Shin1,*, Ji-Sun Kim1,*, Seong-Wook Park1, Sei-Yong Jun1, Hye-Jin Kweon1, Dong-Ki Choi2, Dakeun Lee3, Yong Beom Cho4,5 and Yong-Sung Kim1,6,†
1 Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea.
2 Orum Therapeutics Inc., Daejeon 34050, Republic of Korea.
3 Department of Pathology, Ajou University School of Medicine, Suwon 16499, Republic of Korea.
4 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
5 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Republic of Korea
6 Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon 16499, Republic of Korea.
* These authors contributed equally to this work.
† Corresponding author : Yong-Sung Kim
Abstract
Oncogenic RAS mutant (RASMUT) proteins have been considered undruggable via conventional antibody regimens owing to the intracellular location restricting conventional-antibody accessibility. Here, we report a pan-RAS–targeting IgG antibody, inRas37, which directly targets the intracellularly activated form of various RASMUT subtypes after tumor cell–specific internalization into the cytosol to block the interactions with effector proteins, thereby suppressing the downstream signaling. Systemic administration of inRas37 exerted a potent antitumor activity in a subset of RASMUT tumor xenografts in mice, but little efficacy in RASMUT tumors with concurrent downstream PI3K mutations, which were overcome by combination with a PI3K inhibitor. The YAP1 protein was up-regulated as an adaptive resistance-inducing response to inRas37 in RASMUT-dependent colorectal tumors; accordingly, a combination of inRas37 with a YAP1 inhibitor manifested synergistic antitumor effects in vitro and in vivo. Our study offers a promising pan-RAS–targeting antibody and the corresponding therapeutic strategy against RASMUT tumors.
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