PRP4K IS A NOVEL HER2-REGULATED MODIFIER OF ANOIKIS AND TAXANE RESISTANCE

Abstract

PRP4K is an essential kinase identified in Schizosaccharomyces pombe for its role in regulating pre-mRNA splicing. In addition to its role in splicing, mammalian PRP4K has also been implicated in mitotic checkpoint signaling, host-viral interactions and the cellular response to several anti-cancer therapies. Work presented in this thesis furthers our understanding of the role of PRP4K in cancer treatment and identifies a novel role for PRP4K with implications in cancer progression and relapsed disease. A positive correlation between PRP4K and expression of the human epidermal growth factor receptor HER2 was identified in breast and ovarian cancer patient tumours, and shown to be a direct result of PRP4K regulation by HER2 signaling. Knock-down of PRP4K expression reduced the sensitivity of breast and ovarian cancer cell lines to the taxane family of anti-cancer agents, while low PRP4K levels correlated with in vitro-derived and patient-acquired taxane resistance. Furthermore, high PRP4K expression correlated with better overall survival amongst patients with HER2low high-grade serous ovarian cancer treated with platinum/taxane-based therapy. Therefore, PRP4K functions as a HER2-regulated modifier of taxane sensitivity and may have prognostic value as a marker of better overall survival in taxane-treated ovarian cancer patients. To aid in the study of tumour-drug interactions, a zebrafish xenotransplant model was developed which can be used to quantify proliferation rates of human cancer cells engrafted into zebrafish embryos. Unexpectedly, knock-down of PRP4K led to an increased proliferation of breast and ovarian cancer cell lines within zebrafish embryos, which was shown to be due to an increased resistance to anoikis. Loss of PRP4K prevents degradation of caveolin-1 in cells grown under conditions of low attachment which prevents detachment-induced apoptosis and promotes cell growth within three-dimensional microenvironments, like that of the zebrafish embryo. Collectively, these results demonstrate that downregulation of PRP4K is a potential mechanism through which tumours can acquire a resistance to taxanes. Strikingly, our results also indicate that loss of PRP4K protects cells against detachment-induced cell death, which could contribute to metastatic disease post therapy.