Drug adapted colorectal cancer cell lines as a model of acquired resistance

The formation of acquired resistance to anti-cancer therapies after an initial response is a main reason for the failure of cancer treatments. Drug-adapted cancer cell lines serve as preclinical models to study the mechanisms behind the development of acquired drug resistance and have been demonstrated to mirror the resistance mechanisms observed in clinical settings. Here, we introduce a novel panel of drug-adapted colorectal cancer cell lines consisting of HT29, LoVo, RKO and their sublines adapted to 5-fluorouracil (HT29r5FU100 , LoVor5FU200, RKOr5U500), and oxaliplatin (HT29rOXALI2000, LoVorOXALI4000, RKOrOXALI1500), and irinotecan (LoVor IRINO200, RKOr IRINO2000). However, we haven’t developed any of drug adapted cell lines mentioned here. HT29 was obtained from DSMZ (Braunschweig, Germany), RKO was derived from ATCC and LoVo was derived from ICLC, Genova, Italy and its drug adapted LoVo sublines were derived from the Resistant Cancer Cell Line (RCCL) collection (details discussed in methodology). The determination of cell line morphology, doubling times, and response profiles to 5-fluorouracil, oxaliplatin, cisplatin, irinotecan, and miyabeacin revealed complex profiles among the resistant sublines. This suggests that every resistance formation follows a unique, individual pattern. In agreement, the further adaptation of HT29r5FU100 to higher 5-fluorouracil concentrations resulted in sublines with varying phenotypic profiles. Establishment of drug adapted cell line with resistance to cytotoxic anti-cancer drugs typically takes about a year. Finally, the analysis of single-cell derived clonal sublines of HT29 and HT29r5FU100 indicated a noticeable level of intra-cell line heterogeneity in HT29r5FU100. In conclusion, this study introduces a novel set of colorectal cancer cell lines with acquired resistance to 5-fluorouracil, oxaliplatin, and irinotecan, three drugs that are typically used for the treatment of this cancer type. Characterisation of these cell lines revealed substantial heterogeneity among the drug-resistant sublines, consistent with previous studies