Abstract 6939: MAPKAP kinase 2 regulates inflammatory responses in glioblastoma
Authors: Eleni Panagioti, Yi Wen Kong, Xueyang Yu, Sean E. Lawler, Michael B. Yaffe, Charles H. Cook
Journal: Cancer Research (2025)

Abstract IDH-wildtype glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, with 5-year survival rates of only 6% and a median survival of 14-22 months, depending on the MGMT promoter methylation status. Despite advances in treatment, GBM remains highly resistant due to its complex molecular landscape, characterized by rapid proliferation, angiogenesis, immune invasion, and metabolic dysregulation. In this study, we investigate the role of MAPK-activated protein kinase 2 (MK2), a critical kinase in the MAPK signaling pathway, as a potential therapeutic target in GBM. MK2 regulates key cellular processes including inflammation, stress response, DNA damage repair, and cell migration, all of which contribute to GBM progression. Notably, MK2 is highly enriched in microglia and peripherally derived macrophages. Our results demonstrate that MK2 is significantly upregulated in GBM tissues compared to normal brain tissue, and its expression correlates with poor survival outcomes. In vitro, MK2 inhibition significantly suppresses glioma cell proliferation, induces G1 cell cycle arrest, and promotes apoptosis, suggesting its potential to limit tumor growth and metastasis. To assess the in vivo antitumor effects of MK2 inhibition, we orthotopically implanted GL261 and CT-2A gliomas in MK2 knockout (KO) and wild-type C57BL/6 mice. MK2 genomic knockout is well tolerated in immunocompetent C57BL/6 mice. GL261 tumor cells with intact MK2 signaling effectively implant in hosts with global MK2 deficiency and shows more aggressive tumor growth than in hosts with wild-type MK2. In contrast, there was no effect on tumor growth in the CT-2A model, suggesting that tumor immunogenicity may influence the role of MK2 signaling in GBM. Mechanistically, host MK2 deficiency leads to increased circulating Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs) and elevated PD-L1 expression on these cells, indicating a tumor-promoting inflammatory response and an altered immune profile within the myeloid compartment. These findings suggest an important role of MK2 in immune responses to GBM tumors that restricts growth. Ongoing studies are investigating the immunoregulatory function of MK2 using conditional knockout models targeting MK2 specifically in myeloid cells, as well as selective silencing of MK2 in tumor cells through CRISPR/Cas9 in vivo. Together, our results highlight MK2 as a possible therapeutic target in GBM, and underscores the importance of tumor-selective MK2 inhibitors and targeted therapies. These approaches could serve as adjunctive treatments to overcome therapy resistance and improve patient outcomes in this devastating malignancy. Citation Format: Eleni Panagioti, Yi Wen Kong, Xueyang Yu, Sean E. Lawler, Michael B. Yaffe, Charles H. Cook. MAPKAP kinase 2 regulates inflammatory responses in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6939.