Modification of Brain Tumour Cell Migration via MEK Inhibitors

Abstract

Glioblastoma (GBM) is an aggressive and heterogeneous primary brain tumour in adults. The current multimodal treatment includes surgical resection, chemotherapy, and radiotherapy. However, most patients experience recurrence, which is in part due to the highly migratory nature of GBM and the presence of glioblastoma stem-like cancer cells (GCSs) that exhibit stem-cell-like qualities and resistance against radiation and chemotherapy. Migratory molecules, such as polysialic acid neural cell adhesion molecule (PSA-NCAM), matrix metalloproteinases-9 (MMP-9) and phosphorylated focal adhesion kinase (pFAK), are considered to be involved in tumour cell migration. In addition, recent studies have highlighted associations between mitogen-activated protein/extracellular-signalling related kinase (MEK/ERK) cascade and GBM cell migration. This thesis aimed to investigate the effects of MEK inhibitors trametinib and U0126 on patient-derived GBM cells for the potential attenuation of tumour cell migration. Both Trametinib and U0126 target the MEK-1 and MEK-2 subset and ultimately, inhibit downstream ERK phosphorylation and signalling. pERK and EdU assays were used to determine concentrations that effectively limited proliferation and had minimal toxicity. The concentrations were then administrated to tumour monolayered and spheroid cells in various experimentations including live cell, immunocytochemistry, western blot, qRT-PCR. Overall, trametinib was more effective at inhibiting GBM tumour cell migration compared to U0126, and this finding was consistent across all experimental data. Some migratory markers displayed consistent changes when treated with trametinib, while others produced variable responses. However, no significant relationship was found between the chosen migratory markers and tumour cell migration in the presence of MEK inhibitors. Future prospects include repetition of experimentation in various patient-derived GBM cases and consideration of the tumour microenvironment and biology.