Investigating molecular mechanisms underlying resistance to notch inhibitors in breast and ovarian cancer için kapak resmi
Investigating molecular mechanisms underlying resistance to notch inhibitors in breast and ovarian cancer
Başlık:
Investigating molecular mechanisms underlying resistance to notch inhibitors in breast and ovarian cancer
Yazar:
Telli, Kübra, author.
Yazar Ek Girişi:
Fiziksel Tanımlama:
xx, 219 leaves: charts;+ 1 computer laser optical disc.
Özet:
Breast and ovarian cancers remain highly malignant among women with more than 11% overall of incidence rates worldwide. Traditional treatment strategies including chemotherapy, radiotherapy and hormone therapies continues to be successful yet for the long-term, cancer recurrence and drug resistance remains to be the main issue. In addition to the altering common cell fate regulations, cancer cells modify signaling pathways to overcome cytotoxicity. Notch signalling pathway is a conserved ligand-receptor pathway that necessarily plays role in survival homeostasis, yet it is dysregulated in various cancers. Currently, novel treatment strategies are targeting this pathway through Gamma Secretase Inhibitors (GSI) DAPT, R04929097 and MK0752 that are use both as a single agent and in combinations with Docetaxel or Cisplatin. The clinical success of these inhibitors requires further examination of potential intrinsic or acquired resistance profiles. In this study, we generated breast cancer cells (MDA-MB-231 and MCF-7) resistant to DAPT or R04929097 and ovarian cancer cells (IGROV-1, BG-1, SKOV-3 and A2780) resistant to MK0752 by gradual treatments of increasing doses based on drugs’ IC50 values. Morphological changes, growth rates, migration alterations, mRNA expressions of Notch pathway components and epithelial mesenchymal transition markers, 3D setups for acidosis responses and protein expressions for c-myc and oxidative stress response markers were analyzed. Furthermore, proteomic analysis was carried out with the ovarian cancer cell line IGROV-1. The response of the cells to different drug treatments and dysregulated protein families exposed in resistance mechanisms behind DAPT, R04929097 and MK0752 for both breast and ovarian cancer cells are reported. Overall, this study reveals possible resistance mechanisms against GSIs and emphasizes potential targets through well-known hallmarks of cancer drug resistance.
Yazar Ek Girişi:
Tek Biçim Eser Adı:
Thesis (Doctoral)--İzmir Institute of Technology:Molecular Biology and Genetics.

İzmir Institute of Technology: Molecular Biology and Genetics --Thesis (Doctoral).
Elektronik Erişim:
Access to Electronic Versiyon.
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