Efficacy of SOAT1 Inhibitors Against Pancreatic Cancer with TP53 Mutations.

Abstract

Mutations in TP53 are associated with a poor prognosis in pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated the relationship between TP53 mutations and lipid metabolism abnormalities caused by sterol O-acyltransferase 1 (SOAT1). We hypothesized that SOAT1 inhibitors would show high efficacy in patients with PDAC with TP53 mutations. We performed SOAT1 immunohistochemistry staining of PDAC clinical tissue samples with next-generation sequencing-based comprehensive genomic profiling. We also confirmed the inhibitory effect of SOAT1 using siRNA and avasimibe in vitro and in vivo on pancreatic cancer cells of various TP53 states. We confirmed the mechanism using RNA sequencing analysis. We identified a positive correlation between TP53 mutations and high SOAT1 expression. Notably, the prognosis of PDAC was worse in the presence of TP53 mutation than in the presence of wild-type TP53. Cell proliferation was more strongly suppressed in mutant p53 cells than in wild-type p53 and p53 null cells. Furthermore, we demonstrated that these observations were due to the presence of mutant p53 by adjusting the background via the introduction of mutant TP53. Antitumor efficacy resulting from SOAT1 inhibition was analyzed using RNA sequencing, and cell cycle suppression was observed only in mutant p53 cells. Our results demonstrated that SOAT1 was upregulated in PDAC with TP53 mutations and that SOAT1 inhibition was more effective in TP53-mutated PDAC. These findings would aid in the development of targeted therapeutic strategies against PDAC with TP53 mutations.