Abstract A008: Disruption of SLFN5 enhances vulnerability to APR-246, a mutant p53 reactivator in glioblastoma

Abstract

Abstract Glioblastoma multiforme (GBM) or grade 4 IDHWT glioma is the most malignant brain tumor with a median survival of ~15 months. Current treatment options are limited to a combination of surgery, radiation, and the alkylating agent temozolomide (TMZ). However, despite this aggressive treatment regimen, patients inevitably develop recurrent tumors, which depict a high degree of resistance to DNA damage induced by TMZ and irradiation. Therefore, it is imperative to better understand cellular signals contributing to GBM tumorigenesis and therapy resistance. We have previously established potential roles for members of the protein family of schlafens (SLFNs) in GBM. SLFNs have established roles in cell differentiation, cell proliferation, immune responses, and an expanding role in cancer biology. Several human SLFNs have been linked to chemosensitivity in various cancer types. In particular, SLFN5 mRNA levels progressively increased from grade 2 to grade 4 glioma suggesting a possible therapeutic target for GBM. Therefore, in an effort to better understand the role of SLFN5 in GBM tumorigenesis, CRISPR/Cas9-mediated SLFN5 knockout glioblastoma cell lines and PDX lines were generated. Cells lacking expression of SLFN5 showed increased DNA damage signaling, as judged by elevated basal levels of the DNA damage marker γH2AX and persistent phosphorylation of Chk2. Gene ontology analysis indicated increased expression of p53 pathway components in SLFN5 knockout cells. In GBM, p53 activity is commonly deregulated due to high mutations in the p53 pathway. In line with this, SLFN5 knockout cells depicted increased sensitivity to the mutant p53 reactivator APR-246 correlating with p53 mutational status. APR-246 induced PARP cleavage in SLFN5 knockout cells was rescued by the ROS scavenger N-acetyl-D-cysteine (NAC). Our results suggest increased DNA damage signaling in SLFN5 deficient cells. Furthermore, mutant p53 reactivator APR-246 induced apoptosis is dependent on ROS signaling. In summary, we provide evidence for a protective role of SLFN5 to limit DNA damage and ROS signaling in GBM. Citation Format: Ricardo E. Perez, Frank Eckerdt, Leonidas C. Platanias. Disruption of SLFN5 enhances vulnerability to APR-246, a mutant p53 reactivator in glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A008.