(629b) The role of IRE1? and its downstream pathways in DNA damage repair response and the development of temozolomide-resistance glioblastoma

Glioblastoma multiforme (GBM) is the most aggressive and common primary brain tumor in adults. Standard treatment for GBM combines the oral alkylating agent temozolomide (TMZ) with radiation and surgery. However, a major challenge in treating GBM is tumor recurrence due to development of TMZ-resistance. TMZ elicits cellular toxicity by generating genotoxic stress that eventually leads to apoptosis. Multiple DNA damage repair (DDR) pathways are linked to the development of TMZ-resistance in GBM. Interestingly, the tumor microenvironment may play a role in shaping therapeutic responses of GBM. For example, fatty acid levels are elevated in malignant glioma tissue as compared to normal tissues. Also, changes in fatty acid metabolism of cancer cells are associated with therapeutic resistance through enhanced DDR activity. To engineer better therapeutics for GBM will require a better understanding of how GBM enhances its DDR activity to combat therapeutic stress in a tumor microenvironment. Our laboratory previously showed that the saturated fatty acid palmitate (PA) activates a pro-survival mechanism that promotes cancer progression and metastasis. This activation occurs via IRE1α, an ER stress sensor protein. In this study, we investigated whether IRE1α mediates GBM tolerance towards TMZ through activation of DDR pathways. Our results will demonstrate that PA’s activation of IRE1α contributes to increasing DDR activity and GBM tolerance towards TMZ. The significance of this finding could lead to a novel molecular target for treating TMZ-tolerant GBM.