Investigation of drug-adapted cancer cell lines as pre-clinical models of acquired resistance

Drug-adapted cancer cell lines have been successfully used to identify clinically relevant drug resistance mechanisms. This project focused on the further development of drug-adapted cancer cell lines as pre-clinical models of acquired drug resistance in cancer. A new cell line panel consisting of the ovarian cancer cell lines EFO-21, EFO-27, and COLO-704 and their cisplatin-adapted sublines was introduced and characterised. In addition, doxorubicin-loaded human serum albumin (HSA) nanoparticles were shown to circumvent ABCB1-mediated drug efflux. Vincristine- but not doxorubicin-adapted cells were re-sensitised to the level of the respective parental cells by HSA nanoparticle-incorporated doxorubicin. This indicates that rational strategies to overcome drug resistance in cancer depend on an intimate understanding of (the complexity of) the underlying resistance mechanisms. Finally, a standardised treatment protocol revealed differences in the potential of the microtubule-stabilising agents; docetaxel, paclitaxel, cabazitaxel, and epothilone B to induce resistance in the neuroblastoma cell line UKF-NB-3. In conclusion, this project has contributed to resistance research in cancer by introducing novel models, by providing novel insights into the prospects and limitations of strategies to overcome resistance mediated by transporter-mediated drug efflux, and by developing a novel strategy to assess the potential of anti-cancer drugs to induce resistance.