Resistance patterns in drug-adapted cancer cell lines reflect complex evolution in clinical tumors

Here, we introduce a novel set of drug-adapted triple-negative breast cancer (TNBC) cell lines consisting of the parental cell lines MDA-MB-468, HCC38, and HCC1806 and their sublines adapted to cisplatin, doxorubicin, eribulin, paclitaxel, gemcitabine, or 5-fluorouracil. Whole exome sequencing in combination with the analysis of TCGA-derived patient data resulted in the identification of 135 biomarker candidates for the guidance of personalized TNBC therapies for further investigation, including 58 novel ones that had not been associated with drug resistance before. The analysis of exome sequencing data showed remarkably few overlaps among the resistant sublines, suggesting that each resistance formation process follows an individual, unpredictable route. This complexity was confirmed by cancer cell line drug sensitivity profiles to cytotoxic anti-cancer drugs and DNA damage repair inhibitors. Drug-adapted sublines of the same parental cell line and sublines adapted to the same drug substantially differed in their drug response patterns. Cross-resistance levels were lowest for the CHK2 inhibitor CCT241533, the PLK1 inhibitor SBE13, and the RAD51 recombinase inhibitor B02, making CHK2, PLK1, and RAD51 promising drug targets for therapy-refractory TNBC. In conclusion, we present novel preclinical models of acquired drug resistance in TNBC and 58 novel candidate biomarkers for further investigation. Whole exome data and drug sensitivity profiles showed that each cancer cell line adaptation process follows an unpredictable route, which reflects recent findings on cancer cell evolution in patients, supporting the relevance of drug-adapted cancer cell lines as preclinical models of acquired resistance. ### Competing Interest Statement The authors have declared no competing interest.