Dataset Information

Park2019 - Cetuximab resistance in colorectal cancer

ABSTRACT: It's an experimental + mathematical paper explaining probable targets for Cetixumab resistance in colorectal cancer.

SUBMITTER: Krishna Kumar Tiwari

PROVIDER: MODEL1909300004 | BioModels | 2019-09-30

REPOSITORIES: BioModels

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Publications

Systems analysis identifies potential target genes to overcome cetuximab resistance in colorectal cancer cells.

Park Sang-Min SM Hwang Chae Young CY Cho Sung-Hwan SH Lee Daewon D Gong Jeong-Ryeol JR Lee Soobeom S Nam Sohee S Cho Kwang-Hyun KH

The FEBS journal 20190220 7

Cetuximab (CTX), a monoclonal antibody against epidermal growth factor receptor, is being widely used for colorectal cancer (CRC) with wild-type (WT) KRAS. However, its responsiveness is still very limited and WT KRAS is not enough to indicate such responsiveness. Here, by analyzing the gene expression data of CRC patients treated with CTX monotherapy, we have identified DUSP4, ETV5, GNB5, NT5E, and PHLDA1 as potential targets to overcome CTX resistance. We found that knockdown of any of these f ...[more]

PMID: 30719834

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Project description:Purpose: Irinotecan (SN38) and oxaliplatin are chemotherapeutic agents used in the treatment of colorectal cancer. However, the frequent development of resistance to these drugs represents a considerable challenge in the clinic. Alus as retrotransposons comprise 11% of the human genome. Genomic toxicity induced by carcinogens or drugs can reactivate Alus by altering DNA methylation. Whether or not reactivation of Alus occurs in SN38 and oxaliplatin resistance remains unknown. Methods: We applied reduced representation bisulfite sequencing (RRBS) to investigate the DNA methylome in SN38- or oxaliplatin-resistant colorectal cancer cell line models. Moreover, we extended the RRBS analysis to tumor tissue from 14 patients with colorectal cancer who either did or did not benefit from capecitabine + oxaliplatin treatment. For the clinical samples, we applied a concept of DNA methylation entropy to estimate the diversity of DNA methylation states of the identified resistance phenotype-associated methylation loci observed in the cell line models. Results: We identified different loci being characteristic for the different resistant cell lines. Interestingly, 53% of the identified loci were Alu sequences -- especially the Alu Y subfamily. Furthermore, we identified an enrichment of Alu Y sequences that likely results from increased integration of new copies of Alu Y sequence in the drug-resistant cell lines. In the clinical samples, SOX1 and other SOX gene family members were shown to display variable DNA methylation states in their gene regions. The Alu Y sequences showed remarkable variation in DNA methylation states across the clinical samples. Our findings imply a crucial role of Alu Y in colorectal cancer drug resistance. Our study underscores the complexity of colorectal cancer aggravated by mobility of Alu elements and stresses the importance of personalized strategies, using a systematic and dynamic view, for effective cancer therapy. Investigation of the representive methylome of well-established SN38 and Oxaliplatin resistant cell line models and 14 clinical colorectal metastatic samples that have developed resistance to XELOX to review the epigenetic mechnism of the drug resistance.

Dataset Information

Park2019 - Cetuximab resistance in colorectal cancer

Publications

Systems analysis identifies potential target genes to overcome cetuximab resistance in colorectal cancer cells.

Similar Datasets

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