Epithelial-Mesenchymal plasticity mediates acquired resistance to eribulin in breast cancer
نویسندگان
چکیده
Background: A major obstacle in the fight against cancer is development of drug resistance response to therapy. Metastatic Breast Cancer (MBC) extremely difficult cure, mainly because it driven by tumor cell subpopulations characterized an increased capacity adaptation various stresses. Emerging evidence suggests that epithelial-mesenchymal transition (EMT) program contributes resistance. Therefore, our hypothesis plasticity mediates progression and acquired drugs breast cancer, could be effective approach for therapeutics. Material methods: In this project, we first both cellular molecular effects induced chronic treatment BC cells (MCF7 MDA-MB-231) with approx. IC80 dosage eribulin, focusing on Snail as a driver EM-plasticity escape action eribulin. Then studied RT-PCR expression up-regulation several ABC-transporters mediators mechanism. Finally, performed 3D organoids screening inhibitors (Verapamil, Elacridar, Tariquidar) find possible combinational therapy overcome eribulin Results: We observed after one week treatment, 80% initial die. For about 3 weeks, remaining stay quiescence drug-tolerant persister state (DTP). Then, 1 month from subpopulation starts growing presence drug. These drug-resistant (DR) are highly chemoresistant increasing concentrations they maintain their morphology chemoresistance characteristics even when removed confirming non-reversible phenotype. Interestingly, MCF7 MDA-MB-231 DR populations strongly upregulated EMT-TF Snail. Moreover, analysis confirmed ABCB1, ABCG2, ABCA1 transporters cells. treated combinations different ABC-inhibitors regain sensitivity Conclusions: results provide linking through Snail-driven mechanism mediating specific ABC transporters. expect work will lead new therapeutic tools, where increase success MBC patients. Conflict interest: Other Substantive Relationships: Bruce A. Littlefield full-time employee Eisai Inc.
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ژورنال
عنوان ژورنال: European Journal of Cancer
سال: 2022
ISSN: ['0959-8049', '1879-0852']
DOI: https://doi.org/10.1016/s0959-8049(22)01083-8