Helen E. Grimsley , Magdalena Antczak , Ian G. Reddin , Nicole Weiler , Katie-May McLaughlin , Florian Rothweiler , Johannes Haas , Andrea Nist , Marco Mernberger , Thorsten Stiewe , Tim R. Fenton , Daniel Speidel , Catherine Harper-Wynne , Karina Cox , Dirk Heckl , Jindrich Cinatl , Mark N. Wass , Michelle D. Garrett , Martin Michaelis
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引用次数: 0
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.
期刊介绍:
Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research.
Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy.
By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.