Modelling drug sensitivity and resistance in cancer: Utilising drug-adapted cancer cell lines as a preclinical model

Drug-adapted cancer cell lines are used as a model system of acquired drug resistance in cancer. Here, a newly established set consisting of the non-small lung cancer cell lines HCC4006 and HCC827 and their sublines adapted to the EGFR tyrosine kinase inhibitors afatinib, erlotinib, and gefitinib was characterised. Morphological studies and drug sensitivity profiles indicated a considerable level of heterogeneity among the resistant sublines, indicating that each resistance formation process is unique and the consequence of an unpredictable evolutionary path. Additionally, the impact of the BET inhibitors JQ1 and I-BET726 was determined on cisplatin sensitivity in a panel of cancer cell lines from different cancer types and their sublines adapted to cisplatin. The results were again complex indicating differences between the individual cell lines and the BET inhibitors. Notably, both BET inhibitors consistently sensitised the neuroblastoma cell line UKF-NB-3 and its cisplatin-resistant subline to cisplatin. In conclusion, the characterisation of a new set of EGFR tyrosine kinase inhibitor-adapted non-small cell lung cancer cell lines and the evaluation of the BET inhibitors JQ1 and I-BET726 in cisplatin-adapted cancer cell lines from different cancer entities revealed a high level of heterogeneity among the drug resistant sublines, which reflects the unpredictable nature of cancer evolution in the clinical setting. Further research will have to show whether BET inhibitors also sensitise other neuroblastoma cell lines to cisplatin.