Abstract 5490: Comparative activation of cellular ISR and cell death induction by p53 pathway restoring small molecules

Abstract

Abstract Restoration of the p53 pathway has been a long-term goal of the field of cancer research as an approach to treat tumors with mutated p53 and aggressive clinical behavior. In general, p53- pathway-restoring can be achieved by small molecules through p53-dependent or p53-independent ways. For short, hereafter p53-independent restoration of p53-pathway-signaling is also referred as ‘restoration of p53 pathway’. To perform a comparative activation of p53 target genes, novel compounds PG3 and PG3-Oc that activate a subset of p53-target genes in a p53-independent manner, and four known mutant p53-activating compounds were included (ZMC1, APR-246, CP-31398 and Ellipticine). Nutlin-3a was used as a negative control. PG3 and PG3-Oc induced significant upregulation of p21, PUMA (p53 upregulated modulator of apoptosis), and DR5 consistently in five tested cancer cell lines with various p53 status through ATF4 (Activating transcriptional factor 4) via the ISR in a p53-independent manner. However, mutant p53-targeting compounds induced the expression of the three p53 target genes and ATF4 in a highly variable and cell type-dependent manner. PG3 treatment activated ATF4 through the ISR via kinase HRI (Heme-regulated inhibitor). ATF4 mediated the upregulation of PUMA, p21 and NAG-1 (Nonsteroidal anti-inflammatory drug-activated gene 1). We identified PUMA-mediated cell apoptosis through activation of caspase-8 in HT29 cells and possibly caspase-10 in SW480 cells. In summary, we provide a new mechanism that PG3 induced cell death via an HRI/ATF4/PUMA axis that may be helpful in understanding drug efficacy. Citation Format: Xiaobing Tian, Wafik S. El-Deiry. Comparative activation of cellular ISR and cell death induction by p53 pathway restoring small molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5490.