Pharmacologic and genetic inhibition of cholesterol esterification reduces tumour burden: a pan-cancer systematic review and meta-analysis of preclinical models

Websdale, A.; Kiew, Y.; Chalmers, P.; Chen, X.; Cioccoloni, G.; Hughes, T. A.; Luo, X.; Mwarazi, R.; Poirot, M.; Roberg-Larsen, H.; Wu, R.; Xu, M.; Zulyniak, M. A.; Thorne, J. L.

doi:10.1101/2021.06.12.448188

bioRxiv · 10.1101/2021.06.12.448188

Pharmacologic and genetic inhibition of cholesterol esterification reduces tumour burden: a pan-cancer systematic review and meta-analysis of preclinical models

Websdale, A.·Kiew, Y.·Chalmers, P.·Chen, X.·Cioccoloni, G.·Hughes, T. A.·Luo, X.·Mwarazi, R.·Poirot, M.·Roberg-Larsen, H.·Wu, R.·Xu, M.·Zulyniak, M. A.·Thorne, J. L.

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Abstract

Cholesterol esterification proteins Sterol-O acyltransferases (SOAT) 1 and 2 are emerging prognostic markers in many cancers. These enzymes utilise fatty acids conjugated to coenzyme A to esterify cholesterol. Cholesterol esterification is tightly regulated and enables formation of lipid droplets that act as storage organelles for lipid soluble vitamins and minerals, and as cholesterol reservoirs. In cancer, this provides rapid access to cholesterol to maintain continual synthesis of the plasma membrane. In this systematic review and meta-analysis, we summarise the current depth of understanding of the role of this metabolic pathway in pan-cancer development. A systematic search of PubMed, Scopus, and Web of Science for preclinical studies identified eight studies where cholesteryl ester concentrations were compared between tumour and adjacent-normal tissue, and 24 studies where cholesterol esterification was blocked by pharmacological or genetic approaches. Tumour tissue had a significantly greater concentration of cholesteryl esters than non-tumour tissue (p<0.0001). Pharmacological or genetic inhibition of SOAT was associated with significantly smaller tumours of all types (p[≤]0.002). SOAT inhibition increased tumour apoptosis (p=0.007), CD8+ lymphocyte infiltration and cytotoxicity (p[≤]0.05), and reduced proliferation (p=0.0003) and metastasis (p<0.0001). Significant risk of publication bias was found and may have contributed to a 32% overestimation of the meta-analysed effect size was overestimated. Avasimibe, the most frequently used SOAT inhibitor, was effective at doses equivalent to those previously reported to be safe and tolerable in humans. This work indicates that SOAT inhibition should be explored in clinical trials as an adjunct to existing anti-neoplastic agents.

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Websdale, A., Kiew, Y., Chalmers, P., Chen, X., Cioccoloni, G., Hughes, T. A., Luo, X., Mwarazi, R., Poirot, M., Roberg-Larsen, H., Wu, R., Xu, M., Zulyniak, M. A., Thorne, J. L.. 2021-06-14. Pharmacologic and genetic inhibition of cholesterol esterification reduces tumour burden: a pan-cancer systematic review and meta-analysis of preclinical models. https://doi.org/10.1101/2021.06.12.448188

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