The study of acquired drug resistance in cancer cell lines

Cytotoxic drugs are frequently used in the treatment of cancer. However whilst most patients initially respond well to cytotoxic therapies, acquired resistance often develops. In this project we aim to improve understanding of the mechanisms of acquired drug resistance and contribute to the development of a novel assay for determining the potential of different cancer drugs to cause acquired resistance.

UKF-NB-3 cell lines, initially sensitive to docetaxel, paclitaxel, cabazitaxel and epothilone-b, were cultivated in the presence of each drug. Once resistance was conferred in the surviving sub-lines, the concentration of drug was increased to determine the extent of resistance. The sub-lines of UKF-NB-3 demonstrated resistance to Docetaxel and Paclitaxel. However, cabazitaxel and epothilone-b sub-lines were unable to adapt to the respective drugs. This demonstrates that resistance is more easily acquired to docetaxel and paclitaxel than cabazitaxel and epothilone b. To investigate the resistance mechanism responsible, cross resistance against a panel of selected cytotoxic drugs was determined. The surviving cell lines were resistant to additional drugs with high affinity to ABCB1 transporters. The expression of the drug efflux proteins (ABCB1) and tubulin was determined using confocal microscopy and found to be overexpressed in the resistant sub-lines.

This project will lead to a standard protocol for determining the potential of anti-cancer drugs to cause acquired resistance in cancer cells. In this study we have acquired evidence that cultivation of UKF-NB-3 cell line in higher concentrations of docetaxel can result in increased degrees of resistance, possibly depending on the heterogeneity of the cell population. We have additionally characterised the mechanism of resistance through investigation of ATP-binding cassette (ABC) transporters and tubulin expression. With further work, this project will lead to improved understanding of resistance to tubulin binding agents, the cellular pathways responsible and ultimately improved therapeutic strategies and for drug adaptation of cell lines.