Targeting non-oncogenic kinases DYRK1A and MK2 in glioblastoma

Abstract

Glioblastoma represents the most common and aggressive primary brain tumour. Current treatment protocols however are mostly ineffective as all patients succumb to the disease within two years of diagnosis. Despite continued research and medical advances, patient survival has stagnated. Hence, there is an urgent need for better treatment strategies to combat this devastating disease. Due to their involvement in the progression of cancers, kinases are an important class of drug targets in oncology. Identification of new targets is crucial for the improvement of glioblastoma patient survival. This thesis investigated the potential of targeting two non-oncogenic kinases DYRK1A and MK2. DYRK1A regulates a myriad of signalling pathways some of which are involved in tumourigenesis. The data presented in this thesis characterised two analogues 9h and 10a with potent in vitro inhibition of the DYRK family of kinases. Our work revealed that classical and mesenchymal glioblastoma subtypes which comprise >60% of glioblastomas are sensitive to pan-DYRK inhibitors. Additionally, the mechanism of action of analogues 9h and 10a were unveiled. Another non-oncogenic kinase to have diverse roles in cancer progression is MK2. Herein this thesis, we show that MK2 inhibition strongly attenuates glioblastoma cell proliferation in a p53-dependent manner. Mechanistically, it was unveiled that MK2 stabilised p53wt leading to senescence, which was particularly strong when co-treated with temozolomide. The combination of MK2 inhibition alongside standard-of-care temozolomide provides a new therapeutic strategy to enhance the effectiveness of chemotherapy. MK2 represents a novel drug target in 70% of glioblastomas harbouring intact TP53 gene. This study has also shed light on the effect of different TP53 status on the outcome of inhibiting MK2 in combination with chemotherapy. These findings are highly relevant since TP53 mutations occur in over 50% of cancers. Collectively, these findings help evolve the current understanding of targeting two promising kinase targets DYRK1A and MK2. The comprehensive cellular data gathered in this thesis provides solid ground for further preclinical research into targeting non-oncogenic kinases with the ultimate goal of improving glioblastoma survival rates.