Cetuximab, a chimeric human mouse anti-epidermal growth factor receptor monoclonal antibody, in the treatment of human colorectal cancer

Galizia, Gennaro; Lieto, Eva; Vita, Ferdinando De; Orditura, Michele; Castellano, Paolo; Troiani, Teresa; Imperatore, Vincenzo; Ciardiello, Fortunato

doi:10.1038/sj.onc.1210381

Cited by 140 publications

(90 citation statements)

References 32 publications

(43 reference statements)

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“…Each treatment group consisted of 8 mice. Tumor size was evaluated twice per week by calliper measurements using the following formula: p/6 Â larger diameter Â (smaller diameter) 2 . The animals were sacrificed when the tumor diameter exceeded 1,500 mm 3 .…”

Section: Translational Relevancementioning

confidence: 99%

“…Recent therapeutic strategies for metastatic colorectal cancer (mCRC) have been focused on developing molecularly targeted therapies. The EGFR is expressed in 60% to 80% colorectal cancer and plays a key role in the development and progression of human cancers and for this reason it has been proposed as a target for anticancer therapies (2,3). Cetuximab, an anti-EGF receptor (EGFR) blocking monoclonal antibody (mAb), is an effective treatment as single agent and in combination with standard chemotherapy regimens for patients with KRAS wild-type mCRC (4).…”

Section: Introductionmentioning

confidence: 99%

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Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells

Troiani

Martinelli

Napolitano

et al. 2013

Clinical Cancer Research

132

145

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Purpose: Although cetuximab, an anti-EGF receptor (EGFR) monoclonal antibody, is an effective treatment for patients with KRAS wild-type metastatic colorectal cancer (mCRC), its clinical use is limited by onset of resistance.Experimental Design: We characterized two colorectal cancer models to study the mechanisms of acquired resistance to cetuximab.Results: Following chronic treatment of nude mice bearing cetuximab-sensitive human GEO colon xenografts, cetuximab-resistant GEO (GEO-CR) cells were obtained. In GEO-CR cells, proliferation and survival signals were constitutively active despite EGFR inhibition by cetuximab treatment. Whole gene expression profiling identified a series of genes involved in the hepatocyte growth factor (HGF)-MET-dependent pathways, whichwere upregulated in GEO-CR cells.Furthermore,activated, phosphorylated MET was detected in GEO-CR cells. A second colorectal cancer cell line with acquired resistance to cetuximab was obtained (SW48-CR). Inhibition of MET expression by siRNA restored cetuximab sensitivity in GEO-CR and SW48-CR cells, whereas exogenousactivation ofMETbyHGFstimulationin cetuximab-sensitiveGEOandSW48cells inducedresistance to cetuximab. Treatment of GEO-CR and SW48-CR cells with PHA665752, a selective MET inhibitor, inhibited cell growth, proliferation, and survival signals and impaired cancer cell migration. Overexpression of TGF-a, a specific EGFR ligand, was involved in the acquisition of cetuximab resistance in GEO-CR and SW48-CR cells. In fact, TGF-a overexpression induced the EGFR-MET interaction, with subsequent MET phosphorylation and activation of MET downstream effectors in GEO-CR and SW48-CR cells.Conclusions: These results suggest that overexpression of TGF-a through induction of EGFR-MET interaction contributes to cetuximab resistance in colorectal cancer cells. The combined inhibition of EGFR and MET receptor could represent a strategy for preventing and/or overcoming cetuximab resistance in patients with colorectal cancer.

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Section: Translational Relevancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells

Troiani

Martinelli

Napolitano

et al. 2013

Clinical Cancer Research

132

145

View full text Add to dashboard Cite

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“…Cetuximab, the first chimeric monoclonal antibody which has been generated against the EGFR, is the first-line treatment used as a single agent or in combination with standard chemotherapy for KRAS wild-type mCRC patients (5). The mechanism of cetuximab (C225, Erbitux) involves the specific binding of the extracellular domain of EGFR, subsequently blocking the downstream signaling of EGFR that influences cell proliferation, survival, apoptosis, migration and tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells

Wang

Zhang

et al. 2015

Oncology Reports

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Abstract. Paxillin (PXN) encodes a 68-kDa focal adhesionassociated protein and plays an important role in signal transduction, regulation of cell morphology, migration, proliferation and apoptosis. The aim of the present study was to evaluate the relationship between PXN and clinicopathological factors in colorectal cancer, the role of PXN in cetuximab resistance, and whether knockdown of PXN expression could improve the sensitivity to cetuximab in colorectal cancer cells. In the present study, immunohistochemical staining in 148 colorectal carcinoma and 126 normal adjacent tissues was performed, which showed that the positive rate of PXN was significantly higher in the colorectal adenocarcinoma samples than that in the normal colorectal mucosa samples (P<0.001). Moreover, PXN presence was also positively correlated with TNM stage (P=0.023), distant metastasis (P=0.014), recurrence (P=0.032) and reduced survival (P=0.004). In vitro, PXN expression was positively correlated with the proliferation rate in colorectal cells insensitive to cetuximab. Inhibition of PXN expression by PXN-siRNA clearly increased apoptosis by downregulating the phosphorylation of extracellular signal regulated kinase (p-Erk) level, and overexpression of PXN by PXN-cDNA decreased apoptosis by upregulating the p-Erk level. This suggests that overexpression of PXN could be one of the reasons for cetuximab resistance, and downregulation of PXN plays an important role in improving sensitivity to cetuximab by suppressing the activitation of p-Erk in colorectal cancer cells. Above all, knockdown of PXN could represent a rational therapeutic strategy for increasing the sensitivity or overcoming cetuximab-resistance in patients with colorectal cancer.

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“…In general, the molecular mechanisms that control CRC progression are related to the altered expression of different proto-oncogenes, tumor suppressor genes, cytokines and their receptors, including Ras, Src, p27 kip1 , p16 ink4a , interleukin (IL) and the epidermal growth factor receptor (EGFR). [1][2][3][4][5][6][7] Notably, these abnormalities involve the signal transducers and activators of transcription (STAT) signaling pathway, specifically STAT3 and STAT5 signaling, although very few studies have reported the abnormal expression or activation of STAT proteins in colorectal cancer. 8 Understanding the molecular mechanisms of STATs may further the development of novel therapies targeted in CRC treatment.…”

mentioning

confidence: 99%

Inhibition of STAT5 induces G1 cell cycle arrest and reduces tumor cell invasion in human colorectal cancer cells

Xiong

Liang

et al. 2009

Laboratory Investigation

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Abnormalities in the signal transducer and activator of transcription (STAT) pathway are involved in the oncogenesis of several cancers. However, the mechanism by which dysregulated STAT5 signaling contributes to the progression of human colorectal cancer (CRC) has not been elucidated. To investigate the role of STAT5 in CRC progression, we depleted STAT5 with a small interfering RNA (siRNA). Our results demonstrate that STAT5 is involved in CRC cell growth, cell cycle progression, invasion and migration through regulation of gene expression, such as Bcl-2, p16 ink4a , p21 waf1/cip1 , p27 kip1 , E-cadherin, the focal adhesion kinase (FAK), vascular endothelial growth factor (VEGF) and matrix metalloproteinases. In addition, immunohistochemical staining reveals upregulation of STAT5 during CRC tumorigenesis. Moreover, phospho-STAT5 (pSTAT5) is predominantly localized in the cytoplasm of adenomas cells and colon adenocarcinoma cells, but primarily presented in the nucleus of normal colonic epithelium cells. Thus, pSTAT5 protein is shuttled from the nucleus to the cytoplasm in the oncogenesis of CRC, suggesting that activated STAT5 may also have cytoplasmic functions. In support of this hypothesis, we found that STAT5 formed a complex with p44/42 MAPK and SAPK/JNK in CRC cells, suggesting cross talk between STAT5 signaling and the MAPK pathway in the development of human CRC. Our findings illustrate the biological significance of STAT5 signaling in CRC progression, and provide novel evidence that intervention in STAT5 signaling may have potential therapeutic value in the prevention of human colorectal cancer.

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Cetuximab, a chimeric human mouse anti-epidermal growth factor receptor monoclonal antibody, in the treatment of human colorectal cancer

Cited by 140 publications

References 32 publications

Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells

Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells

Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells

Inhibition of STAT5 induces G1 cell cycle arrest and reduces tumor cell invasion in human colorectal cancer cells

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