Targeting the p38 MAPK-MK2 pathway for glioblastoma therapy

Abstract

Glioblastoma is the most lethal and prevalent form of brain cancer. Its therapy is not only limited in its choices but also in extending life expectancies of patients. Identification of genetic aberrations driving tumour growth and progression have leveraged our understanding of the inherent complexity of this cancer. Cell cycle dysregulation, apoptotic resistance and inflammatory tumour microenvironment have emerged as key processes that surmount glioblastoma therapy success. Due to their vast involvement in hallmark phenotypes of tumour biology, kinases are becoming important drug targets in oncology. The p38 mitogen-activated protein kinase (MAPK) and its downstream MAPK-activated protein kinase 2 (MK2) regulate a myriad of signalling pathways influencing inflammation, cell death, differentiation and motility that allow cells to respond to external cues. Recent evidence suggests that these kinases could contribute to tumourigenesis and chemotherapy resistance. This thesis aims to investigate whether targeting the p38 MAPK-MK2 pathway is a viable therapeutic approach for glioblastoma therapy and to elucidate the contribution of these kinases to pathophysiology of the disease. Data presented herein describes how MK2 mediates EGFRvIII oncogene-induced inflammation. Opposing roles of p38 MAPK and MK2 in cell cycle progression and survival of glioblastoma cells are revealed for the first time with important implications for temozolomide chemotherapy response. Moreover, we provide evidence that selective targeting of MK2 is a promising strategy to circumvent the pro-tumourigenic contribution of this pathway in glioblastoma. Finally, this thesis discloses in vitro characterisation of commercially available MK2 inhibitor denoted CMPD1 and highlights the importance of target validation for kinase inhibitors before advancing to clinical/research settings. Structural analogues of CMPD1 with potential for glioblastoma therapy have been identified.