Abstract B17: Targeting MK2 to improve temozolomide efficacy in glioblastoma

Glioblastoma is the most prevalent and aggressive form of brain cancer. The heterogeneous nature and survival mechanisms that glioblastoma tumors develop impede chemotherapy efficacy of temozolomide (TMZ) and result in tumor relapse. The p38 MAPK and its downstream kinase MK2 have been well established in regulating signaling pathways influencing inflammation, cell division and differentiation, as well as cell motility in response to a wide range of extracellular stimuli. Recent studies have identified p38 MAPK-MK2 pathway as an effector kinase complex that is activated following DNA damage and results in cell cycle arrest, so that cells have the capacity to repair their DNA and continue to proliferate. Importantly, cells with p53 mutation/deficiency were shown to rely on MK2 pathway for G2/M arrest and survival after exposure to chemotherapy and thus highlighting MK2 as a potential therapeutic target.We sought to determine if inhibition of MK2 in glioblastoma cells would result in increased efficacy of TMZ and to delineate the underlying mechanisms. Using genetic knockdown and pharmacological inhibitors we examined whether MK2 inhibition improves temzolomide efficacy in glioblastoma cell lines and patient-derived tumor cells of different subtypes (classical, mesenchymal, proneural and neural). Viability and clonogenic assays were used to determine survival of tumor cells to combination treatment. Apoptosis was determined using Annexin-V staining, cell cycle analysis using fl...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Replication Stress and DNA Damage Response: Poster Presentations - Proffered Abstracts Source Type: research