Investigation of the drug resistance in capecitabine resistant hct-116, dabrafenib resistant ht-29, and sn-38 resistant ht-29 cell lines using cellular barcoding technology

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2022-11-3

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Baygın, Rana Can

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Cancer is a complex disease, and understanding its biology holds great importance. Tumor cells exhibit hallmarks of cancer, including aberrantly activated signaling pathways and gain or loss genomic alterations that result in alterations in their differentiation programs, survival, proliferation, and programmed cell death. Developing resistance to therapeutic agents is one of the major problems in cancer therapies. Exploiting drug resistance using the principles of clonal evolution can pave the way to overcoming or controlling drug resistance in cancers. Collateral sensitivity as a second-line therapy strategy positively impacts the treatment of cancer, and it could offer novel therapeutic strategies to overcome or control drug resistance. In this study, it was aimed to monitor the development of drug resistance using cellular barcoding technology to identify second-line therapeutic agents that sensitize initially drug-resistant cell populations. To develop the evolutionaryinformed strategy for drug resistance and to study the effect of second-line therapy in colorectal cancer cell lines, barcoded HCT-116 and HT-29 cell lines were used. The barcode analysis showed that the capecitabine resistance in HCT-116 cells was caused by de novo, dabrafenib resistance in HT-29 cells was caused by de novo, and the SN-38 resistance in HT-29 cells was caused by pre-existing alterations in the population. The cell viability assays of drug-resistant cells indicated that collateral sensitivity exists for other drugs. Thus, the development of drug resistance in colorectal cancer cells was associated with pre-existed or de novo mutations depending on a cell line or a drug in the preferred experimental model system and potentially had a great impact on mediating collateral sensitivity as a second-line therapy option.

Subject Keywords

Colorectal cancer, drug resistance, collateral sensitivity, second-line therapies

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https://hdl.handle.net/11511/101129

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Graduate School of Natural and Applied Sciences, Thesis

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Citation Formats

R. C. Baygın, “Investigation of the drug resistance in capecitabine resistant hct-116, dabrafenib resistant ht-29, and sn-38 resistant ht-29 cell lines using cellular barcoding technology,” M.S. - Master of Science, Middle East Technical University, 2022.