Puvanenthiran, Soozana (2016) Growth factor receptors, cancer stem cells and drug resistance antigens : their roles in the progression of ovarian cancer and response to therapeutics. (PhD thesis), Kingston University, .
Abstract
Ovarian cancer is one of the most aggressive and lethal types of gynaecological cancer. In the past two decades, increased expression and activation of HER (human epidermal growth factor receptor) family members have been reported in a wide range of epithelial tumours, and in some studies they have been associated with a poorer prognosis. To date, several monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKis) specific for the HER members have been approved for the treatment of patients with a wide range of tumours, but none has yet been approved for the treatment of patients with ovarian cancers. The aim of this study was to determine the sensitivity of a large panel of human ovarian cancer cell lines (OCCLs) to treatment with various forms of HER tyrosine kinase inhibitors (TKis), including reversible EGFR specific, and reversible and irreversible pan-ErbB family inhibitors. In addition, the effect of other inhibitors including Dasatinib (v-abl/src/c-KIT TKI), Imatinib (v-abl/c-KIT/PDGFR TKI), NVP-AEW541 (I GF-1 R inhibitor), Crizotinib ( c-MET / ALKinhibitor) and cytotoxic agents (pacl itaxel, cisplatin and doxorubicin) on the growth of OCCLs was investigated. Any association between the expression of various biomarkers, such as the putative ovarian cancer stem cell (CSC) markers (e.g. CD24, CD44, and CDl 17/c-KIT), P-Glycoprotein (Pgp), and HER family members and their responses to treatment with these agents were examined. Of the HER inhibitors, the irreversible pan-TKis ( canertinib, neratinib and afatinib) were the most effective TKI's for inhibiting the growth of all OCCLs, and for blocking the phosphorylation of EGFR, HER-2, AKT and MAPK in SKOV3 cells. Interestingly, while the majority of cancer cells were highly sensitive to treatment with dasatinib, they were relatively resistant to treatment with imatinib (i.e. IC50> 10 µM). Of the cytotoxic agents, paclitaxel was the most effective for inhibiting the growth of OCCLs, and of various combinations of these drugs, only treatment with a combination of NVP-AEW541 and paclitaxel produced a synergistic or additive anti-proliferative effect in all three cell lines examined (i.e. SKOV3, Caov3 and ES2). Of the TKis, only treatment with afatinib, neratinib and dasatinib were able to reduce the migration of HER-2 overexpressing SKOV3 cells. Interestingly, while acquired resistant of ovarian cancer cells to treatment with afatinib and dasatinib was accompanied by cross-resistance to other TKis, such resistant variants become more sensitive to killing by cytotoxic drugs. No signification association was found between the expression of putative ovarian CSC markers, HER family members, and other markers on the response to the treatment with the TKis. The expression pattern and prognostic significance of the HER-family members, EGFRvIII, CD44, IGF-lR, c-MET and Ki67 were also examined in tumour specimens from 60 FIGO stage III and IV ovarian cancer patients. The expression of EGFR, HER-2, HER-4, c-MET, CD44 and Ki67 was found to be common in patients with FIGO stage III and IV ovarian cancer. EGFR and CD44 expression at cut-off values of >50% and >50% of tumour cells with positive staining were associated with poorer overall survival, whilst Ki67 at cut off value of >5% was associated with fav6urable overall survival. In conclusion, the results presented support the need for further investigations of the therapeutic potential of the irreversible HER family blockers in ovarian cancer, and the therapeutic potential of dasatinib when used in combination with the inhibitors of the HER family members.
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