Abstract B027: Synergy between ONC201 and temozolomide on ATF4 integrated stress response in glioblastoma

Abstract

Abstract Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults with a median survival time of 15 months. The standard of care involves surgical resection followed by chemoradiotherapy. Even with the full course of treatment, GBM is uncurable, and patients eventually relapse. Although temozolomide (TMZ) is the first-choice chemotherapeutic for GBM, tumor drug resistance limits the effects of the treatment. There is a growing need for new therapies with enhanced efficacy on GBM tumors. ONC201 is a TNF-related apoptosis-inducing ligand (TRAIL)-inducing compound that is increasingly being studied for GBM treatment. This small molecule induces apoptosis by activating the integrated stress response, which involves transcription factors ATF4 and CHOP. Subsequently, these transcription factors upregulate proapoptotic protein TRAIL and its receptor, Death Receptor 5 (DR5). This study aims to investigate the combinatory effects of chemotherapeutics ONC201 and TMZ on GBM. Preliminary studies examined the cell viability of GBM cell line U251MG using ONC201 concentrations up to 40uM and TMZ concentrations up to 200uM. Additionally, western blots performed with 0, 2, and 4uM of ONC201 in combination with 0 and 120uM of TMZ demonstrated greater ATF4 expression when both drugs were administered concurrently than when either drug was administered alone. Subsequent western blots were conducted using three GBM cell lines (U251MG, T98G, and SNB19-GFP) at three time points (8, 24, and 48 hours). All cell lines were treated with 0 and 4uM of ONC201 in combination with 0 and 120uM of TMZ. At all three time points and for all three cell lines, ATF4 expression increased in the combined presence of TMZ and ONC201. However, the effects of TMZ on ONC201-induced ATF4 expression were most pronounced in U251MG. These observations suggest synergy between chemotherapeutics ONC201 and TMZ in the ATF4 integrated stress response pathway in GBM. By exploring the effects of this dual treatment on upstream and downstream factors in the integrated stress response pathway, we can identify, characterize, and potentially target the root cause of this synergy. Citation Format: Josephine Chen, Andrew George, Lanlan Zhou, Wafik El-Deiry. Synergy between ONC201 and temozolomide on ATF4 integrated stress response in glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B027.