Abstract
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.
Highlights
At initial diagnosis, approximately 20% of colorectal cancer (CRC) patients present with distant dissemination, which is associated with a high mortality rate, highlighting the importance of effective systemic therapeutic strategies [1,2]
In contrast to previous studies, we utilized the patient-derived xenografts (PDXs) platform to evaluate the efficacy of GC1118 and its mechanism of action, as the induction and expression of high-affinity Epidermal growth factor receptor (EGFR) ligands have been reported to be more prevalent in CRC tumor xenografts than in in vitro cultures [8]
GC1118 is a human anti-EGFR IgG1 antibody that differs from existing anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab and panitumumab, in its constant region, affinity, mode of action, and efficacy [8,20], exhibiting superior binding affinity to both the low- and high-affinity variants of FcγRIIIa compared to cetuximab [8,20]
Summary
Approximately 20% of colorectal cancer (CRC) patients present with distant dissemination, which is associated with a high mortality rate, highlighting the importance of effective systemic therapeutic strategies [1,2]. Activating mutations in the KRAS proto-oncogene GTPase (KRAS) are most common among CRCs, comprising approximately 35%–45% of alterations (point mutations in exons 2, 3, and 4) [12,13,14,15], and these predict primary resistance to anti-EGFR MoAbs, such as cetuximab and panitumumab [16,17,18,19] This is because constitutively activated RAS downstream signaling can activate multiple processes involved in tumor progression without the influence of EGFR and related receptor kinases [5,10]. There is circumstantial evidence to suggest that an excess of high-affinity ligands drives resistance to cetuximab [6,8,20,21]
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