SOAT1 promotes mevalonate pathway dependency in pancreatic cancer

Area of Science:

• Oncology
• Metabolic Pathways
• Cancer Biology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, necessitating novel therapeutic strategies.
• Altered cellular metabolism represents a vulnerability in cancer, with several pathways implicated in PDAC progression.
• The specific alterations in cholesterol metabolism and their functional role in PDAC progression are not well understood.

Purpose of the Study:

• To investigate the drivers of altered cholesterol metabolism in PDAC.
• To determine the impact of disrupting cholesterol metabolism on PDAC tumor progression.
• To identify potential therapeutic targets within cholesterol metabolic pathways.

Main Methods:

• Utilized organoid and mouse models of pancreatic cancer.
• Investigated the role of sterol O-acyltransferase 1 (SOAT1) in cholesterol homeostasis.
• Assessed the effects of SOAT1 inhibition on cell proliferation and tumor growth.
• Examined the dependency on the mevalonate pathway in p53-mutant PDAC cells.

Main Results:

• Identified SOAT1 as a key enzyme converting cholesterol to cholesterol esters, preventing feedback inhibition of the mevalonate pathway.
• Genetic targeting of SOAT1 significantly impaired PDAC cell proliferation in vitro and tumor progression in vivo.
• Demonstrated a specific dependency on the mevalonate pathway in PDAC cells with p53 mutations and loss of heterozygosity (LOH).
• Found that PDAC organoids without p53 mutations or LOH were resistant to SOAT1 inhibition.

Conclusions:

• SOAT1 plays a critical role in sustaining the mevalonate pathway in certain PDAC contexts.
• Inhibition of SOAT1 presents a potential therapeutic strategy for PDAC, particularly in tumors with p53 alterations.
• The findings suggest a targeted therapeutic window for SOAT1 inhibitors in a subset of PDAC patients.