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Title: The role of HER-targeted tyrosine kinase inhibitors in the treatment of high grade serous ovarian cancer
Author: Bonello, Maria
ISNI:       0000 0004 8509 3700
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2020
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High-grade serous ovarian cancer (HGSOC) has the highest incidence rate of the various subtypes of ovarian cancer. HGSOC patients usually respond to initial platinum therapy, however approximately 70% of patients relapse, or worse, become resistant to therapy. Members of the Human Epidermal growth factor Receptor (HER) family, especially EGFR and HER2, are frequently involved in disease progression, hence strategies to inhibit their action could prove advantageous as treatment for selected ovarian cancer patients. Monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) targeted against the HER family have demonstrated valuable anti-tumour activity in multiple other cancer types, and their possible use in ovarian cancer merits further study. This study sought to evaluate the effectiveness of HER-targeted therapy in platinum-resistant and platinum-sensitive HGSOC, and the implications of HER family expression and other biomarkers in response to treatment. The effects of five TKIs (afatinib, canertinib, lapatinib, neratinib and sapitinib) targeted against multiple HER family members on cellular functionality were studied in three pairs of HGSOC cell lines, wherein each pair was derived from the same patient before and after clinical resistance to platinum-based chemotherapy. The effects of the TKIs were compared with the anti-HER2 mAbs trastuzumab and pertuzumab. The outcomes of modulation of EGFR, HER2 and HER3 expression on treatment sensitivity were also investigated, along with gene expression differences upon treatment. The TKIs were found to be effective in inhibiting proliferation, migration and invasion, even in the presence of epidermal growth factor (EGF) and heregulin (HRG). The mAbs investigated were not as effective as the TKIs. Combination strategies of TKI with cytotoxic agents (cisplatin, carboplatin and paclitaxel) and TKI with mAbs were compared for their anti-proliferative behaviour. Combinations involving neratinib with pertuzumab or cisplatin demonstrated a degree of synergy. Knock-down of EGFR expression affected the anti-migratory effects of neratinib, but did not influence its anti-proliferative activity. Overexpression of HER2 or HER3 in the platinum-sensitive cell lines caused these cells to become more sensitive to TKIs, whilst the contrary happened when HER2 or HER3 were overexpressed in the platinum-resistant cell lines. The MAPK pathway was stimulated by EGF and HRG, as was the PI3K pathway. Protein expression through western blot analysis showed that neratinib decreased phosphorylation of ERK and Akt in the cell lines. Neratinib was the most potent TKI of those tested in growth inhibition studies, and was used to investigate the effects of TKI treatment on gene expression. Neratinib down-regulated the MAPK and PI3K pathways in most cell lines, even in the presence of HRG, whilst reducing proliferation and migration processes. Based on gene expression data, CCAAT Enhancer Binding Protein Gamma (CEBPG), DNA Damage Inducible Transcript 4 Like (DDIT4L), Ral guanine nucleotide dissociation stimulator (RALGDS), and Sprouty homolog 2 (SPRY2) were identified as possible HER-targeted therapy-induced biomarkers, whose expression changed upon neratinib-treatment from this data set, and mAb-treatment based in another data set. Assessment of these proteins in tissue microarrays consisting of ovarian cancer xenografts treated with mAbs over a period of days, identified higher expression in the mAb-treatment group than the controls for all proteins except SPRY2, which had lower expression. In conclusion, treatment with HER-targeted TKIs could be a useful approach even in the treatment of platinum-resistant HGSOC, where the expression of EGFR, HER2 and HER3 play an important role in determining TKI sensitivity.
Supervisor: Langdon, Simon ; Sims, Andrew Sponsor: European Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: ovarian cancer ; tyrosine kinase inhibitors ; HGSOC ; neratinib ; platinum-resistant ; HER-targeted