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Promising Therapeutic Efficacy of GC1118, an Anti-EGFR Antibody, against KRAS Mutation-Driven Colorectal Cancer Patient-Derived Xenografts.

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.

SUBMITTER: Lee HW

PROVIDER: S-EPMC6928876 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Promising Therapeutic Efficacy of GC1118, an Anti-EGFR Antibody, against KRAS Mutation-Driven Colorectal Cancer Patient-Derived Xenografts.

Lee Hye Won HW Son Eunju E Lee Kyoungmin K Lee Yeri Y Kim Yejin Y Lee Jae-Chul JC Lim Yangmi Y Hur Minkyu M Kim Donggeon D Nam Do-Hyun DH

International journal of molecular sciences 20191124 23

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 <i>KRAS</i> 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 ...[more]

PMID: 31771279

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Project description:BackgroundColorectal cancer (CRC) is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies (both acquired and intrinsic), owing to the amplification or mutation of the KRAS oncogene. However, the mechanism underlying this resistance is incompletely understood.MethodsDLD1 cells with WT (+/-) or KRAS G13D mutant allele were treated with different concentrations of Cetuximab (Cet) or panitumumab (Pab) to study the mechanism underlying the KRAS mutation-induced resistance to anti-EGFR antibodies. The function of AMPK in KRAS mutation-induced resistance to anti-EGFR antibodies in CRC cells, and the regulatory role of Bcl-2 family proteins in DLD1 cells with WT or mutated KRAS upon AMPK activation were investigated. In addition, xenograft tumor models with the nude mouse using DLD1 cells with WT or mutated KRAS were established to examine the effects of AMPK activation on KRAS mutation-mediated anti-EGFR antibody resistance.ResultsHigher levels of AMPK activity in CRC cells with wild-type KRAS treated with anti-EGFR antibody resulted in apoptosis induction. In contrast, CRC cells with mutated KRAS showed lower AMP-activated protein kinase (AMPK) activity and decreased sensitivity to the inhibitory effect of anti-EGFR antibody. CRC cells with mutated KRAS showed high levels of glycolysis and produced an excessive amount of ATP, which suppressed AMPK activation. The knockdown of AMPK expression in CRC cells with WT KRAS produced similar effects to those observed in cells with mutated KRAS and decreased their sensitivity to cetuximab. On the contrary, the activation of AMPK by metformin (Met) or 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) could overcome the KRAS-induced resistance to the anti-EGFR antibody in vivo and in vitro. The activation of AMPK resulted in the inhibition of myeloid cell leukemia 1 (Mcl-1) translation through the suppression of the mammalian target of rapamycin (mTOR) pathway.ConclusionThe results established herein indicate that targeting AMPK is a potentially promising and effective CRC treatment strategy. Video abstract.

Dataset Information

Promising Therapeutic Efficacy of GC1118, an Anti-EGFR Antibody, against KRAS Mutation-Driven Colorectal Cancer Patient-Derived Xenografts.

Publications

Promising Therapeutic Efficacy of GC1118, an Anti-EGFR Antibody, against KRAS Mutation-Driven Colorectal Cancer Patient-Derived Xenografts.

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