Stanley, Aryan Edward (2017) Growth factor receptors, HPV and drug-resistance antigens : their roles in the progression of breast cancer and response to therapeutics. (PhD thesis), Kingston University, .

Abstract

Despite recent advances in diagnosis and treatment of breast cancer, it still has the highest incidence and mortality of any cancer among women worldwide, and is responsible for more than half a million deaths every year. In recent decades, increased expression and activation of the human epidermal growth factor receptor (HER) family members has been identified in a wide range of cancers. In particular, HER2 is overexpressed in around 25% of all breast cancers and is often associated with poor patient prognosis. As a result, a number of anti-cancer agents targeting HER2 and other members of the HER-family have been approved for the treatment of breast cancer, including the anti-HER2 monoclonal antibodies trastuzumab and pertuzumab, the reversible dual EGFR/HER2 small molcule tyrosine kinase inhibitor (TK1) lapatinib, the antibody-drug conjugate T-DM1, and, more recently, the irreversible pan-HER TK1 neratinib. Despite these advances, however, many patients with HER2 positive (HER2+) breast cancer do not respond to treatment, and many who do later relapse with acquired resistance to the original treatment. The aim of this study was to investigate the sensitivity of a large panel of breast cancer cell lines to treatment with various types of HER-family TKIs, including reversible EGFR-specific, dual EGFR/HER2, and pan-HER TKIs, and irreversible pan-HER TKIs. Additionally the effect of other TKIs with differing targets, including imatinib (BCR-Abl/c-Kit/PDGFR TKI), dasatinib (BCR-Abl/c-Kit/Src TKI), NVP-AEW541 (IGF-1R TKI), crizotinib (ALK/c-Met TKI), and the chemotherapeutic agents paclitaxel and gemcitabine, on the growth of these breast cancer cell lines was also investigated. The association between receptor tyrosine kinase expression and sensitivity of breast cancer cell lines to these agents was also assessed. Furthermore, the mechanisms of action of these agents and their effect on downstream signalling, cell cycle distribution and cell migration were also examined. Of the HER-family TKIs, the second-generation irreversible pan-HER TKIs, particularly afatinib and neratinib, were more effective at inhibiting growth and migration of breast cancer cell lines compared with the first-generation reversible inhibitors (e.g. erlotinib, lapatinib, sapitinib). Furthermore, the irreversible pan-HER TKIs were more effective than the reversible HER-family TKIs at inhibiting phosphorylation of HER-family members and downstream signalling molecules Akt and MAPK. Of the other TKIs, dasatinib was the most effective at inhibiting growth and migration of breast cancer cells, particularly the triple negative cell line MDA-MB-231. Of the chemotherapeutic agents, paclitaxel was the most consistently effective at inhibiting growth of breast cancer cell lines. Combined treatment of TKIs and chemotherapeutic agents were synergistic in some breast cancer cell lines, but no combination was synergistic in all the cell lines tested. Acquired resistance to both lapatinib and afatinib was accompanied by cross-resistance to all other HER-family TKIs and increased sensitivity to dasatinib and gemcitabine. No significant association was found between the expression levels of HER-family members and response to treatment, with the surprising exception of the irreversible pan-HER TKI canertinib. In addition, the role of human papillomavirus (HPV) in breast cancer was also investigated using breast cancer tissue arrays, and of 100 breast cancer tissue samples examined, 24 were found to be positive for the high-risk HPV oncoprotein E7. However, no association was found between E7 positivity and the expression of EGFR, HER2, oestrogen receptor (ER) or progesterone receptor (PR). Further investigations into the potential of irreversible pan-HER TKIs and the BCR-Abl/c-Kit/Src inhibitor dasatinib,as well as the potential benefits of using HER-family TKIs in combination with dasatinib, NVP-AEW541 and gemcitabine, in the treatment of different subtypes of breast cancer are warranted.

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