Abstract 393: RAS and PI3K activation promote glioblastoma progression and ischemia-associated tumor cell death

Abstract

Abstract Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor in adults. Despite the association of tumor necrosis and a poor prognosis in GBM, the mechanisms underlying tumor necrosis formation remain unclear, likely due to the lack of appropriate experimental models to examine the development of tumor necrosis. In our study, we developed mouse models with tumor necrosis by intracranially injecting human GBM cells expressing KRAS or PI3K active mutants into immunodeficient mice. Surprisingly, despite all tumors displayed similar sizes, the control tumors expressing an empty vector (EV) did not exhibit tumor necrosis. This intriguing observation led us to explore the potential role of KRAS and PI3K in promoting cell death within the tumor microenvironment. Ischemia, which is characterized by insufficient nutrients and hypoxia, is often found in GBM. Under an in vitro ischemia mimetic condition, we found that the KRAS or PI3K activated GBM cells showed more cell death compared to EV cells. Mechanistically, ischemia activates the p38 MAPK-MK2 pathway to induce cell death, a process further enhanced by KRAS or PI3K. Notably, we observed elevated expression of p-MK2 in the peri-necrotic areas of GBMs harboring KRAS or PI3K mutants compared to the cellular tumor zones. Moreover, we revealed that ischemia induces the unfolded protein response (UPR) pathway. Among UPR-related molecules, KRAS and PI3K upregulate ERN1, which encodes the transmembrane protein kinase IRE1, in ischemic conditions. Inhibition of ERN1 not only prevented ischemia-induced cell death but also inhibited the p38 MAPK-MK2 pathway. Furthermore, we observed an increase in the expression of pro-inflammatory cytokine IL-8 under ischemic conditions, a response that was prevented by inhibitors of p38 MAPK or MK2. Lastly, we found that ischemia induces ATP release and calreticulin exposure, indicating the cell death possessing certain immunogenic cell death features. In summary, our findings revealed a pivotal role of KRAS and PI3K in inducing cell death in the ischemic GBM tumor microenvironment through activating the IRE1-p38 MAPK-MK2 pathway. The cell death under this circumstance displays pro-inflammatory and immunogenic properties. Therefore, the IRE1-p38 MAPK-MK2 pathway may be exploited for the treatment of GBM in which RAS or PI3K is activated. Citation Format: Soo Yeon Kim, Miaolu Tang, Stephen Chih, Jessica Thorpe, Tong Lu, Hong-Gang Wang, Wei Li. RAS and PI3K activation promote glioblastoma progression and ischemia-associated tumor cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 393.