期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 20, 期 23, 页码 -出版社
MDPI
DOI: 10.3390/ijms20235894
关键词
colorectal cancer; patient-derived xenograft; EGFR-targeting therapeutic antibody; KRAS mutation; PI3K/mTOR/AKT inhibitor
资金
- Bio & Medical Technology Development Program of the National Research Foundation (NRF)
- National Research Foundation of Korea (NRF)
- Ministry of Education, Republic of Korea [NRF-2017R1A2B4011780]
- Korean government (MSIP) [NRF-2016R1A5A2945889]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI)
- Ministry of Health & Welfare, Republic of Korea [HI14C3418]
Epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies, including cetuximab and panitumumab, are used to treat metastatic colorectal cancer (mCRC). However, this treatment is only effective for a small subset of mCRC patients positive for the wild-type KRAS GTPase. GC1118 is a novel, fully humanized anti-EGFR IgG1 antibody that displays potent inhibitory effects on high-affinity EGFR ligand-induced signaling and enhanced antibody-mediated cytotoxicity. In this study, using 51 CRC patient-derived xenografts (PDXs), we showed that KRAS mutants expressed remarkably elevated autocrine levels of high-affinity EGFR ligands compared with wild-type KRAS. In three KRAS-mutant CRCPDXs, GC1118 was more effective than cetuximab, whereas the two agents demonstrated comparable efficacy against three wild-type KRAS PDXs. Persistent phosphatidylinositol-3-kinase (PI3K)/AKT signaling was thought to underlie resistance to GC1118. In support of these findings, a preliminary improved anti-cancer response was observed in a CRC PDX harboring mutated KRAS with intrinsically high AKT activity using GC1118 combined with the dual PI3K/mammalian target of rapamycin (mTOR)/AKT inhibitor BEZ-235, without observed toxicity. Taken together, the superior antitumor efficacy of GC1118 alone or in combination with PI3K/mTOR/AKT inhibitors shows great therapeutic potential for the treatment of KRAS-mutant mCRC with elevated ratios of high- to low-affinity EGFR ligands and PI3K-AKT pathway activation.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据