Solid tumours grow in an interactive milieu of tumour cells and the microenvironment, and it is critical to assess cancer biology and efficacy of novel anti-cancer drugs in this context. Glioblastoma (GBM) is the most common brain tumour in adults with no cure. As inflammation is crucial for development and progression of GBM, we investigated the role of inflammatory MAPK-activated kinase 2 (MK2) in the pathophysiology of GBM microenvironment. Furthermore, MK2 is involved in checkpoint signalling, where it mediates the recruitment of DNA repair pathways in response to chemotherapy. Thus, MK2 has emerged as a target to modulate inflammatory microenvironment and enhance chemosensitivity in cancer cells.
Pharmacological profiling of MK2 inhibitors in multiple in vitro inflammation and proliferation assays employing primary human microglia, astrocytes and GBM cells with varying genomic profile will be presented. Investigation of the molecular mechanism revealed that MK2-dependent nuclear-cytoplasm shuttling of human antigen R (HuR), an mRNA stabilising protein, is responsible for the inflammatory activity in cancer cells. Tested MK2 inhibitors improved chemosensitivity of GBM cells to temozolomide, the standard chemotherapeutic used in GBM therapy. Interestingly, MK2 inhibitors also showed potent anti-proliferative efficacy as single agents. Combined, our data provide first in vitro evidence for MK2 as a biologically relevant molecular target in brain tumours. Development of novel BBB-permeable MK2 inhibitors will also be presented.