Using a novel panel of drug-resistant triple-negative breast cancer cell lines to identify candidate therapeutic targets and biomarkers Journal Article
| Authors: | Grimsley, H. E.; Antczak, M.; Reddin, I. G.; Weiler, N.; McLaughlin, K. M.; Rothweiler, F.; Haas, J.; Nist, A.; Mernberger, M.; Stiewe, T.; Fenton, T. R.; Speidel, D.; Harper-Wynne, C.; Cox, K.; Heckl, D.; Cinatl, J.; Wass, M. N.; Garrett, M. D.; Michaelis, M. |
| Article Title: | Using a novel panel of drug-resistant triple-negative breast cancer cell lines to identify candidate therapeutic targets and biomarkers |
| Abstract: | Here, we introduce a novel set of triple-negative breast cancer (TNBC) cell lines consisting of MDA-MB-468, HCC38, and HCC1806 and their sublines adapted to cisplatin, doxorubicin, eribulin, paclitaxel, gemcitabine, or 5-fluorouracil. Whole exome sequencing combined with TCGA-derived patient data resulted in the identification of 682 biomarker candidates in a pan-cancer analysis. Thirty-five genes were considered the most promising candidates because they harbored resistance-associated variants in at least two resistant sublines, and their expression correlated with TNBC patient survival. Exome sequencing and response profiles to cytotoxic drugs and DNA damage response inhibitors identified revealed remarkably little overlap between the resistant sublines, suggesting that each resistance formation process follows a unique route. This reflects recent findings on cancer cell evolution in patients, supporting the relevance of drug-adapted cancer cell lines as preclinical models of acquired resistance. Moreover, all of the drug-resistant TNBC sublines remained sensitive or even displayed collateral sensitivity to a range of tested compounds. Cross-resistance levels were lowest for the CHK2 inhibitor CCT241533, the PLK1 inhibitor SBE13, and the RAD51 recombinase inhibitor B02, suggesting that CHK2, PLK1, and RAD51 are potential drug targets for therapy-refractory TNBC. In conclusion, we present novel preclinical models of acquired drug resistance in TNBC and the identification of novel candidate therapeutic targets and biomarkers for this disease. © 2025 The Authors |
| Keywords: | controlled study; survival analysis; unclassified drug; human cell; genetics; cisplatin; doxorubicin; antineoplastic agents; gemcitabine; paclitaxel; flow cytometry; antineoplastic agent; biological marker; metabolism; cell viability; dna repair; gene expression; cell growth; caspase 3; drug resistance; pathology; drug resistance, neoplasm; cell line, tumor; tumor marker; polo like kinase 1; cancer cell; tumor cell line; western blotting; dna damage response; checkpoint kinase 2; drug therapy; rad51 protein; eribulin; triple negative breast cancer; minichromosome maintenance protein 7; caspase 7; peptides and proteins; gene ontology; tcga; cancer prognosis; humans; human; female; article; exome sequencing; rna sequencing; fluorouridine; breast cancer cell line; ic50; acquired drug resistance; mtt assay; whole exome sequencing; biomarkers, tumor; crispr-cas9 system; triple negative breast neoplasms; mda-mb-468 cell line; hcc38 cell line; hcc1806 cell line; de novo variants; exome sequencing dna repair; dna topoisomerase 2 alpha; marker of proliferation ki-67; drug resistant triple negative breast cancer cell lines |
| Journal Title: | Cancer Letters |
| Volume: | 624 |
| ISSN: | 0304-3835 |
| Publisher: | Elsevier Ireland Ltd. |
| Date Published: | 2025-08-01 |
| Start Page: | 217754 |
| Language: | English |
| DOI: | 10.1016/j.canlet.2025.217754 |
| PUBMED: | 40300663 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
