MOLECULAR AND CLONAL CHARACTERIZATION OF OXALIPLATIN-RESISTANT HCT116 AND CETUXIMAB-RESISTANT LIM1215 COLORECTAL CANCER CELL LINES UNDER CONTINUOUS AND INTERMITTENT DRUG EXPOSURE USING CELLULAR DNA BARCODING TECHNOLOGY

Date

2025-8-27

Author

Yılmaz, Gamze

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Colorectal cancer (CRC), one of the most common types of cancer in society, results in fatal cases due to treatment resistances that develop over time, despite the advancements in treatment strategies. Elucidating the mechanisms of drug resistance observed in colorectal cancer patients holds significant importance in preventing the disease from becoming more aggressive and progressing. In addition to existing treatment strategies such as continuous drug administration, a new therapy approach known as intermittent therapy aims to delay the onset of potential drug resistance and control tumour growth by considering the growth dynamics of tumour cells under drug exposure. Furthermore, considering the heterogeneous nature of cancer disease, it is important to uncover the clonal dynamics evolving throughout the resistance process for revealing the mechanisms of drug resistance. The focus of this project is to shed light on the molecular drug resistance mechanisms and to investigate the changing clonal dynamics during resistance development over time in HCT116 and LIM1215 colorectal cancer cell lines treated with oxaliplatin and cetuximab, respectively, through the implementation of continuous and intermittent treatment regimens. Cellular DNA barcoding technology, a novel approach to monitor the alterations of clonal dynamics, was employed to barcode these cells to reveal the drug resistance mechanisms. Following the development of drug resistance in HCT116 and LIM1215 cell lines, mutational profiles of drug-resistant cells were characterised using Whole Exome Sequencing (WES), and transcriptomic changes were determined through RNA sequencing analysis. Additionally, acquired sensitivity of first-line drug-resistant cells to secondary drugs were assessed by a comprehensive drug screening assay.

Subject Keywords

colorectal cancer, drug resistance, continuous and intermittent treatment, barcoding technology

URI

https://hdl.handle.net/11511/116201

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Graduate School of Natural and Applied Sciences, Thesis