Pharmacogenomic Identification of Novel Determinants of Response to Chemotherapy in Colon Cancer

Boyer, Julien; Allen, Wendy L.; McLean, Estelle G.; Wilson, Peter M.; McCulla, Andrea; Allen, Wendy L.; Longley, Daniel B.; Caldas, Carlos; Johnston, Patrick G.

doi:10.1158/0008-5472.can-05-2693

Cited by 95 publications

(95 citation statements)

References 39 publications

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“…This study therefore seeks to develop and understand the cytotoxic effect of 56MESS on eukaryotes at gene expression level by the means of transcriptomics. Transcriptomics, a platform which can reveal changes of gene expression at a genome-wide scale, is a powerful holistic approach to profile gene expression for understanding molecular pathways of preclinical and clinical anticancer drugs [7,23,25]. The model eukaryotic organism, yeast Saccharomyces cerevisiae, plays a significant role in this approach [68] due to its easy amendability with various experimental approaches and conservation of genes and essential cellular functions with humans [3].…”

Section: Introductionmentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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Platinum-based DNA metallointercalators are structurally different from the covalent DNA binders such as cisplatin and its derivatives but have potent in vitro activity in cancer cell lines. However, limited understanding of their molecular mechanisms of cytotoxic action greatly hinders their further development as anticancer agents. In this study, a lead platinum-based metallointercalator, [(5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane) platinum(II)] 2+ (56MESS) was found to be 163-fold more active than cisplatin in a cisplatin-resistant cancer cell line. By using transcriptomics in a eukaryotic model organism, yeast Saccharomyces cerevisiae, we identified 93 genes that changed their expressions significantly upon exposure of 56MESS in comparison to untreated controls (p≤0.05). Bioinformatic analysis of these genes demonstrated that iron and copper metabolism, sulfur-containing amino acids and stress response were involved in the cytotoxicity of 56MESS. Follow-up experiments showed that the iron and copper concentrations were much lower in 56MESS-treated cells compared to controls as measured by inductively coupled plasma optical emission spectrometry. Deletion mutants of the key genes in the iron and copper metabolism pathway and glutathione synthesis were sensitive to 56MESS. Taken together, the study demonstrated that the cytotoxic action of 56MESS is mediated by its ability to disrupt iron and copper metabolism, suppress the biosynthesis of sulfur-containing amino acids and attenuate cellular defence capacity. As these mechanisms are in clear contrast to the DNA binding mechanism for cisplatin and its derivative, 56MESS may be able to overcome cisplatinresistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.

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Section: Introductionmentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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“…Although the development and characterization of oxaliplatin-resistant HCT116 colorectal carcinoma cells by repeated exposure to increasing concentrations of oxaliplatin has been reported previously (Boyer et al, 2004(Boyer et al, , 2006, base excision repair protein levels in oxaliplatin-resistant cancer cells have not been characterized. We found that untreated HCT-OR cells had on average 2.2-fold higher levels of Pol b protein than untreated parental HCT116 cells ( Figure 1a, compare lanes 4 and 1, respectively).…”

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confidence: 99%

Cells deficient in the base excision repair protein, DNA polymerase beta, are hypersensitive to oxaliplatin chemotherapy

et al. 2009

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A significant proportion of human cancers overexpress DNA polymerase beta (Pol b), the major DNA polymerase involved in base excision repair. The underlying mechanism and biological consequences of overexpression of this protein are unknown. We examined whether Pol b, expressed at levels found in tumor cells, is involved in the repair of DNA damage induced by oxaliplatin treatment and whether the expression status of this protein alters the sensitivity of cells to oxaliplatin. DNA damage induced by oxaliplatin treatment of HCT116 and HT29 colon cancer cells was observed to be associated with the stabilization of Pol b protein on chromatin. In comparison with HCT116 colon cancer cells, isogenic oxaliplatin-resistant (HCT-OR) cells were found to have higher constitutive levels of Pol b protein, faster in vitro repair of a DNA substrate containing a single nucleotide gap and faster repair of 1,2-GG oxaliplatin adduct levels in cells. In HCT-OR cells, small interfering RNA knockdown of Pol b delayed the repair of oxaliplatin-induced DNA damage. In a different model system, Pol b-deficient fibroblasts were less able to repair 1,2-GG oxaliplatin adducts and were hypersensitive to oxaliplatin treatment compared with isogenic Pol b-expressing cells. Consistent with previous studies, Pol b-deficient mouse fibroblasts were not hypersensitive to cisplatin treatment. These data provide the first link between oxaliplatin sensitivity and DNA repair involving Pol b. They demonstrate that Pol b modulates the sensitivity of cells to oxaliplatin treatment.

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“…Our data, while not specifically identifying ERCC1 as a candidate hit, did identify numerous genes involved in the repair of DNA damage, including members of the NER (of which ERCC1 is a key molecule) and DNA MMR pathways (Table 1). It is possible that ERCC1 mRNA levels may predict resistance to oxaliplatin only in the clinical setting of combination therapy with 5-FU (42). In our screen, we treated cells with oxaliplatin alone to reduce the identification of false-positive hits and to simplify the screen design.…”

Section: Resultsmentioning

confidence: 99%

Functional Genomics Reveals Diverse Cellular Processes That Modulate Tumor Cell Response to Oxaliplatin

Harradine

Kassner

Chow

et al. 2011

Molecular Cancer Research

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Oxaliplatin is widely used to treat colorectal cancer, as both adjuvant therapy for resected disease and palliative treatment of metastatic disease. However, a significant number of patients experience serious side effects, including prolonged neurotoxicity, from oxaliplatin treatment creating an urgent need for biomarkers of oxaliplatin response or resistance to direct therapy to those most likely to benefit. As a first step to improve selection of patients for oxaliplatin-based chemotherapy, we have conducted an in vitro cell-based small interfering RNA (siRNA) screen of 500 genes aimed at identifying genes whose loss of expression alters tumor cell response to oxaliplatin. The siRNA screen identified twenty-seven genes, which when silenced, significantly altered colon tumor cell line sensitivity to oxaliplatin. Silencing of a group of putative resistance genes increased the extent of oxaliplatin-mediated DNA damage and inhibited cell-cycle progression in oxaliplatin-treated cells. The activity of several signaling nodes, including AKT1 and MEK1, was also altered. We used cDNA transfection to overexpress two genes (LTBR and TMEM30A) that were identified in the siRNA screen as mediators of oxaliplatin sensitivity. In both instances, overexpression conferred resistance to oxaliplatin. In summary, this study identified numerous putative predictive biomarkers of response to oxaliplatin that should be studied further in patient specimens for potential clinical application. Diverse gene networks seem to influence tumor survival in response to DNA damage by oxaliplatin. Finally, those genes whose loss of expression (or function) is related to oxaliplatin sensitivity may be promising therapeutic targets to increase patient response to oxaliplatin. Mol Cancer Res; 9(2); 173-82. Ó2010 AACR.

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Pharmacogenomic Identification of Novel Determinants of Response to Chemotherapy in Colon Cancer

Cited by 95 publications

References 39 publications

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

Cells deficient in the base excision repair protein, DNA polymerase beta, are hypersensitive to oxaliplatin chemotherapy

Functional Genomics Reveals Diverse Cellular Processes That Modulate Tumor Cell Response to Oxaliplatin

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