Targeting the Achilles’ heel – dissecting drug resistance in ovarian cancer

We have shown that the expression of specific proteins, for example the phosphorylated forms of the serine/threonine protein kinase AKT (protein kinase B), is higher in drug resistant cells, thus identifying candidate proteins which can be targeted with highly specific small molecule inhibitors – using the clinical trial drug MK-2206 to inhibit pAKT, for example, allowed us to re-sensitise drug-resistant cells to both carboplatin and paclitaxel chemotherapy. Further analysis of this unique dataset has identified multiple differences in receptor tyrosine kinase signaling pathways in drug-resistant cells, characteristic of phenotypic changes induced by an epithelial-mesenchymal transition, resulting in functionally-important differences in cell morphology, proliferation and metastatic potential. The aim of this translational PhD project will therefore be to use a wide variety of complementary experimental approaches (including qRT-PCR analysis, Western blotting, siRNA-mediated gene knockdowns, chemosensitivity and phenotypic assays) to investigate the role of our prioritised candidate genes in drug resistance, with a particular focus on developing novel combination chemotherapy approaches and quantitative drug resistance biomarkers. Ourin vitro experiments described above will be complemented, in collaboration with our wider clinical research team, by analysis of matched primary ascites-derived cell lines created from initially drug-sensitive and subsequently drug-resistant ovarian cancer patients collected as they progress through treatment in the Dundee Ovarian Cancer Study (DOCS). Availability of DOCS study samples provides a unique opportunity both to further validate prioritised targets in well-characterised clinical samples, and to use the unbiased profiling approaches described above for additional target discovery.