The biological properties of cetuximab

Vincenzi, Bruno; Schiavon, Gaia; Silletta, Marianna; Santini, Daniele; Tonini, Giuseppe

doi:10.1016/j.critrevonc.2008.07.006

Cited by 117 publications

(126 citation statements)

References 82 publications

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“…Several antitumor agents, interfering with the EGFR pathway, have been developed (25). Among them, cetuximab is used for CRC treatment either as a single agent or in combination with chemotherapy (26). The mechanisms through which cetuximab performs its anticancer activity are numerous and not completely understood.…”

Section: Discussionmentioning

confidence: 99%

Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Ragusa¹,

Majorana²,

Statello³

et al. 2010

Molecular Cancer Therapeutics

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The relationship between therapeutic response and modifications of microRNA (miRNA) transcriptome in colorectal cancer (CRC) remains unknown. We investigated this issue by profiling the expression of 667 miRNAs in 2 human CRC cell lines, one sensitive and the other resistant to cetuximab (Caco-2 and HCT-116, respectively), through TaqMan real-time PCR. Caco-2 and HCT-116 expressed different sets of miRNAs after treatment. Specifically, 21 and 22 miRNAs were differentially expressed in Caco-2 or HCT-116, respectively (t test, P < 0.01). By testing the expression of differentially expressed miRNAs in CRC patients, we found that miR-146b-3p and miR-486-5p are more abundant in K-ras-mutated samples with respect to wild-type ones (Wilcoxon test, P < 0.05). Sixty-seven percent of differentially expressed miRNAs were involved in cancer, including CRC, whereas 19 miRNA targets had been previously reported to be involved in the cetuximab pathway and CRC. We identified 25 transcription factors putatively controlling these miRNAs, 11 of which have been already reported to be involved in CRC. On the basis of these data, we suggest that the downregulation of let-7b and let-7e (targeting K-ras) and the upregulation of miR-17* (a CRC marker) could be considered as candidate molecular markers of cetuximab resistance. Global network functional analysis (based on miRNA targets) showed a significant overrepresentation of cancer-related biological processes and networks centered on critical nodes involved in epidermal growth factor receptor internalization and ubiquitin-mediated degradation. The identification of miRNAs, whose expression is linked to the efficacy of therapy, should allow the ability to predict the response of patients to treatment and possibly lead to a better understanding of the molecular mechanisms of drug response.

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Section: Discussionmentioning

confidence: 99%

Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Ragusa¹,

Majorana²,

Statello³

et al. 2010

Molecular Cancer Therapeutics

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“…Cetuximab (also known as Erbitux or C225) is a recombinant chimeric human-murine monoclonal antibody and is among the most promising and clinically effective of these agents (8)(9)(10). Cetuximab binds EGFR with high affinity and prevents receptor activation, thereby suppressing proliferation and angiogenesis and promoting antibody-dependent cellular toxicity (11). When administered in conjunction with the platinum-based chemotherapy drug cisplatin, treatment with cetuximab resulted in a longer overall survival time in patients with recurrent or metastatic head and neck SCC (HNSCC) (12).…”

Section: Introductionmentioning

confidence: 99%

Cetuximab inhibits cisplatin-induced activation of EGFR signaling in esophageal squamous cell carcinoma

et al. 2014

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Abstract.A malignant esophageal cancer, squamous cell carcinoma is one of the most prevalent cancers. Despite the use of present surgical techniques combined with various treatment modalities, the overall 5-year survival rate remains at 15-34%. Epidermal growth factor receptor (EGFR) is the most well studied receptor in various cancers and EGFR overexpression is detected in 40% of esophageal squamous cell carcinomas (ESCCs) and ESCC cell lines. To examine the EGFR antibody combination effect, we used treatment with cisplatin and cetuximab in ESCC cell lines, TE-4 and TE-8. Combination of cetuximab and cisplatin resulted in a growth inhibition only in the EGFR overexpressed TE-8 cell line. Furthermore, we confirmed that cisplatin-induced EGFR activation was inhibited by cetuximab in TE-8 but not in TE-4 cells. Our data suggest that cetuximab combined with cisplatin exerts antitumorigenic effects in vitro and in vivo via suppression of EGF signaling, which can be applied toward targeted ESCC treatments.

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“…42). Cetuximab is a chimeric mouse/human IgG1 with an approximate monovalent affinity of 100 pmol/L (43). Strikingly, all therapeutic anti-EGFR monoclonal antibodies examined showed diminished inhibition of highaffinity ligand-driven ERK signaling regardless of antibody affinity, suggesting a class effect.…”

Section: Monoclonal Antibodies Poorly Inhibit High-affinity Egfr Ligandsmentioning

confidence: 99%

Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic

Kearns

Bukhalid

Sevecka

et al. 2015

Molecular Cancer Therapeutics

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Although EGFR is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest the need for improved therapeutics. Here, we demonstrate that signal amplification driven by highaffinity EGFR ligands limits the capacity of monoclonal anti-EGFR antibodies to block pathway signaling and cell proliferation and that these ligands are commonly coexpressed with low-affinity EGFR ligands in epithelial tumors. To develop an improved antibody therapeutic capable of overcoming high-affinity ligand-mediated signal amplification, we used a network biology approach comprised of signaling studies and computational modeling of receptor-antagonist interactions. Model simulations suggested that an oligoclonal antibody combination may overcome signal amplification within the EGFR:ERK pathway driven by all EGFR ligands. Based on this, we designed MM-151, a combination of three fully human IgG1 monoclonal antibodies that can simultaneously engage distinct, nonoverlapping epitopes on EGFR with subnanomolar affinities. In signaling studies, MM-151 antagonized high-affinity EGFR ligands more effectively than cetuximab, leading to an approximately 65-fold greater decrease in signal amplification to ERK. In cell viability studies, MM-151 demonstrated antiproliferative activity against high-affinity EGFR ligands, either singly or in combination, while cetuximab activity was largely abrogated under these conditions. We confirmed this finding both in vitro and in vivo in a cell line model of autocrine high-affinity ligand expression. Together, these preclinical studies provide rationale for the clinical study of MM-151 and suggest that high-affinity EGFR ligand expression may be a predictive response marker that distinguishes MM-151 from other anti-EGFR therapeutics.

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The biological properties of cetuximab

Cited by 117 publications

References 82 publications

Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Cetuximab inhibits cisplatin-induced activation of EGFR signaling in esophageal squamous cell carcinoma

Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic

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