Gene Polymorphisms of Epidermal Growth Factor Receptor and its Downstream Effector, Interleukin-8, Predict Oxaliplatin Efficacy in Patients with Advanced Colorectal Cancer

Zhang, Wu; Stoehlmacher, Jan; Park, David J.; Yang, Dongyun; E, Borchard; Gil, Ji; Tsao‐Wei, Denice; Yun, Jim; Gordon, Michael A.; Press, O.; Rhodes, Katrin E.; Groshen, Susan; Lenz, Heinz‐Josef

doi:10.3816/ccc.2005.n.025

Cited by 62 publications

(49 citation statements)

References 19 publications

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“…Among all patients assessed, those possessing <20 EGFR CA repeats were more likely to show disease progression than were patients with z20 CA repeats (P < 0.05; Table 2; ref. 57). Taken together, these results suggest that the short CA SSR I intron 1 polymorphism and the resulting higher EGFR expression may predict for worse outcome following conventional therapy.…”

Section: Allelic Length Of the Ca Ssr I Dinucleotide Repeat Along Witmentioning

confidence: 78%

Mechanisms ofegfrGene Transcription Modulation: Relationship to Cancer Risk and Therapy Response

Brandt

Meyer-Staeckling

Schmidt³

et al. 2006

Clinical Cancer Research

101

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The epidermal growth factor receptor (EGFR) plays a crucial role in growth, differentiation, and motility of normal as well as cancer cells. For predictive cancer diagnostics and therapeutic targeting of EGFR, it is important to know how the expression level of EGFR is controlled and related to receptor signaling. A novel transcriptional regulation mechanism has been described that depends on the length of a CA repeat in intron 1 [CA simple sequence repeat 1 (CA SSR I)] of the EGFR gene.Thereby, the number of CA repeats is inversely correlated to pre-mRNA synthesis. Indirect evidence for the importance of this mechanism includes the preferential occurrence of amplifications in cancer tissue harboring short CA repeats in this sequence and the discovery of distinct alleles in young breast cancer patients with a family history of the disease and in Japanese breast cancer patients. It can be postulated that the length of the CA repeat influences DNA bendability and, in consequence, the binding of repressor proteins. In summary, it seems that the CA SSR I represents an inherited variable for response to anti-EGFR therapies that could be determined before therapy. Moreover, the potential for synergistic effects with other polymorphism [e.g., EGFR R497K (HER-1 497K) and CCND1 A870G] leading to a simultaneous increase of EGFR signaling activity and expression should be investigated. From a practical perspective, assessment of the CA SSR I number of CA dinucleotide repeats as a predictor for clinical outcome is very attractive because it is a constant feature that does not change over time and can be easily measured in normal and cancer tissues (blood cells, skin, and tumor biopsies) in an assay that is technically simple, objective, and even quantitative.

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Section: Allelic Length Of the Ca Ssr I Dinucleotide Repeat Along Witmentioning

confidence: 78%

Mechanisms ofegfrGene Transcription Modulation: Relationship to Cancer Risk and Therapy Response

Brandt

Meyer-Staeckling

Schmidt³

et al. 2006

Clinical Cancer Research

101

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“…Our previous data and others have shown that the IL-8/CXCR2 pathway plays a key role in mediating colorectal cancer development (11,14,15,32). In follow-up to our previously published data in colorectal cancer, this study focused on the impact of inhibition of CXCR2 on the proliferation, survival, invasion, and migration in colorectal cancer in vitro and in vivo models.…”

Section: Discussionmentioning

confidence: 90%

“…Previous studies by our group and others have shown that IL-8 and its receptor CXCR2 are significantly upregulated in the tumor and its microenvironment in colorectal cancer (11)(12)(13). These studies showed that expression levels of IL-8 and CXCR2 were associated with tumor proliferation, progression, and sensitivity of oxaliplatin-based therapy in colorectal cancer cell line models and genetic variants in IL-8 and CXCR2 both predict tumor recurrence and oxaliplatin efficacy in patients (11,14,15). It is well known that oxaliplatin-based chemotherapy is a standard of care agent used most commonly in combination with 5-fluorouracil in patients with colorectal cancer (16).…”

Section: Introductionmentioning

confidence: 82%

The CXCR2 Antagonist, SCH-527123, Shows Antitumor Activity and Sensitizes Cells to Oxaliplatin in Preclinical Colon Cancer Models

Ning

LaBonte

Zhang

et al. 2012

Molecular Cancer Therapeutics

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Colorectal cancer is the second most common cause of cancer-related death in the United States. Recent studies showed that interleukin-8 (IL-8) and its receptors (CXCR1 and CXCR2) are significantly upregulated in both the tumor and its microenvironment, and act as key regulators of proliferation, angiogenesis, and metastasis. Our previous study showed that IL-8 overexpression in colorectal cancer cells triggers the upregulation of the CXCR2-mediated proliferative pathway. The aim of this study was to investigate whether the CXCR2 antagonist, SCH-527123, inhibits colorectal cancer proliferation and if it can sensitize colorectal cancer cells to oxaliplatin both in vitro and in vivo. SCH-527123 showed concentration-dependent antiproliferative effects in HCT116, Caco2, and their respective IL-8-overexpressing variants colorectal cancer cell lines. Moreover, SCH-527123 was able to suppress CXCR2-mediated signal transduction as shown through decreased phosphorylation of the NF-kB/mitogen-activated protein kinase (MAPK)/AKT pathway. These findings corresponded with decreased cell migration and invasion, while increased apoptosis in colorectal cancer cell lines. In vivo results verified that SCH-527123 treatment decreased tumor growth and microvessel density when compared with vehicle-treated tumors. Importantly, these preclinical studies showed that the combination of SCH-527123 and oxaliplatin resulted in a greater decrease in cell proliferation, tumor growth, apoptosis, and angiogenesis that was superior to single-agent treatment. Taken together, these findings suggest that targeting CXCR2 may block tumor proliferation, migration, invasion, and angiogenesis. In addition, CXCR2 blockade may further sensitize colorectal cancer to oxaliplatin treatment.

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“…For example, a functional polymorphism (-216 G/T) of the Sp1-binding site in the EGFR promoter correlates with an altered promoter activity and a higher response to chemoradiation in locally advanced rectal cancer patients (17,18). Cells with a lower number of CA dinucleotide repeats in an intron 1 region of the EGFR have a higher expression level (19) and may predict a poor efficacy to oxaliplatin treatment in patients with advanced colorectal carcinoma (20). The A61G polymorphism of EGFR has also been shown as a useful marker for predicting clinical outcome in colorectal carcinoma patients treated with a monoclonal anti-EGFR antibody cetuximab (21).…”

mentioning

confidence: 99%

Epidermal Growth Factor Receptor R497K Polymorphism Is a Favorable Prognostic Factor for Patients with Colorectal Carcinoma

Wang¹,

Chen²,

Chiou³

et al. 2007

Clinical Cancer Research

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Purpose: It has been shown that the R497K polymorphism of the epidermal growth factor receptor (EGFR) has attenuated functions in ligand binding, tyrosine kinase activation, and growth stimulation. Because the activation of EGFR results in an unfavorable prognosis of patients with colorectal carcinoma, a pilot study was conducted to assess the influence of this polymorphism on colorectal carcinoma patients. Experimental Design: We retrospectively analyzed the effect of the R497K polymorphism of EGFR on clinicopathologic features in 209 colorectal carcinoma patients, including100 with stage II/III colorectal carcinoma receiving curative surgery and the other 109 with metastatic diseases. Results: An excellent correlation in codon 497 statuses examined by patients' WBCs and tumor tissues was found but no significant between-group difference in patients with or without colorectal carcinoma (P = 0.97). A marked decrease on EGFR phosphorylation (P < 0.01) and c-Myc activation (P = 0.02) was observed in patients with R497K polymorphism, which is associated with decreased invasion (P = 0.01), lower nodal involvement (P = 0.02), reduced subsequent metastasis (P < 0.01), and longer disease-free (P < 0.01) as well as overall (P < 0.01) survival in stage II/III colorectal carcinoma patients who had received curative surgery. For patients with metastatic colorectal carcinoma, this polymorphism was associated with a higher response to 5-fluorouracil/oxaliplatin treatment (P = 0.02) and a longer survival (P < 0.01). By multivariate analysis, this polymorphism was also identified as an independent prognostic factor (P = 0.03). Conclusions: These data suggest that the R497K polymorphism of the EGFR, by reducing its activation and a consequential down-regulation of its target genes, could be a key determinant for reduced tumor recurrence of stage II/III colorectal carcinoma patients receiving curative surgery and a longer survival of patients with stage II/III as well as metastatic colorectal carcinoma.

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Gene Polymorphisms of Epidermal Growth Factor Receptor and its Downstream Effector, Interleukin-8, Predict Oxaliplatin Efficacy in Patients with Advanced Colorectal Cancer

Cited by 62 publications

References 19 publications

Mechanisms ofegfrGene Transcription Modulation: Relationship to Cancer Risk and Therapy Response

Mechanisms ofegfrGene Transcription Modulation: Relationship to Cancer Risk and Therapy Response

The CXCR2 Antagonist, SCH-527123, Shows Antitumor Activity and Sensitizes Cells to Oxaliplatin in Preclinical Colon Cancer Models

Epidermal Growth Factor Receptor R497K Polymorphism Is a Favorable Prognostic Factor for Patients with Colorectal Carcinoma

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