Can the Dual Inhibition of Extracellular Signal-Related Kinase (ERK) and Phosphoinositide-3 Kinase (PI3K) Increase Efficacy of Cisplatin in Endometrial and Ovarian Cancers?
Thesis DisciplineCellular and Molecular Biology
Degree GrantorUniversity of Canterbury
Degree NameMaster of Science
Ovarian and endometrial cancers are two of the most common gynaecological malignancies in women. The chemotherapeutic drug cisplatin is a first-‐line therapy for both of these cancers, however despite the success of this treatment there are patients who suffer relapse. This is associated with acquired resistance of tumour cells to cisplatin and raises the need for an effective treatment that can re-‐sensitise the cancer to cisplatin. There is promise in targeting particular cellular growth and signalling pathways that contain over active proteins, as it is these that decide a cells fate (in terms of survival or death). This study investigates the inhibition of both the PI3K, Akt, mTOR pathway through phosphoinositide-‐3 kinase (PI3K) and the Ras, Raf, MEK, ERK pathway through extracellular signal-‐related kinase (ERK). The aim of the project is to re-‐sensitize cisplatin resistant cancerous cell lines Hec-‐1A (endometrial adenocarcinoma) and OVCAR-‐5 (ovarian adenocarcinoma) to cisplatin through PI3K and ERK inhibition. The dual inhibition therapy utilized inhibitors FR180204 and LY294002 who target ERK and PI3K respectively. This research utilized 3D cell culturing techniques, which provided an insight into the potential impact a tumour cells microenvironment may have on the treatment. The results of this research found no significant reduction in cellular metabolism or growth activity after treatment with FR180204, LY294002 and cisplatin (singly and in combination). Limited Western blotting of signalling proteins suggested the inhibitors had no significant effect upon the expression of ERK, Akt and cyclin B2 proteins across all combination treatments in OVCAR-‐5 cells. The information provided in this research is capable of providing a platform for future studies investigating resistant cancers using targeted drug therapy and 3D cell culturing techniques.