Abstract 3676: De novo lipogenesis and cholesterol synthesis pathways can be simultaneously targeted to induce metabolic synthetic lethality in prostate cancer

Abstract Aberrant activation of fatty acid synthase (FASN) and de novo lipogenesis (DNL) is a major metabolic event in prostate cancer (PCa). Targeting lipid synthesis through FASN blockade can inhibit prostate tumor growth. Another metabolic pathway commonly altered in PCa is the mevalonate pathway, responsible for the synthesis of cholesterol from acetyl-CoA. The rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), can be targeted with statins, drugs commonly prescribed for the management of hypercholesterolemia. Following FASN inhibition with IPI-9119, genes involved in the mevalonate pathway and cholesterol synthesis are transcriptionally upregulated. Metabolomics data confirmed an increase in intracellular levels of cholesterol after FASN inhibition, suggesting a compensatory mechanism to support PCa cell survival in the absence of de novo synthesized lipids. Interestingly, we also observed an increase in mRNA levels of Acyl-CoA Synthetase Short Chain Family Member 2 (ACSS2), the enzyme that converts acetate into acetyl-CoA. Next, we evaluated how FASN blockade affected acetate utilization by PCa cells and observed that acetate uptake increases with DNL inhibition. Metabolic analysis confirmed that 14C-acetate incorporation into lipids was increased after IPI-9119 treatment. The concomitant inhibition of FASN and HMGCR reduced acetate lipid incorporation, suggesting that acetate is fueling cholesterol synthesis. To better understand this effect, we analyzed the cell membrane after FASN inhibition, and an increase in fluidity was seen, which could be rescued by palmitate. Lipidomics analysis showed an increase in polyunsaturated fatty acids (PUFA) esterified to phospholipids, as well as overall increase in fatty acyl chain length, events that can affect membrane structure and fluidity. Due to the important role of lipids as energy reservoir, we also analyzed the effect of FASN blockade in neutral lipids. IPI-9119 treatment caused depletion of triacylglycerides, while levels of cholesterol esters (CE) and Acetyl-CoA Acetyltransferase 2 (ACAT2), an enzyme involved in CE synthesis, are upregulated. Acyl chain length and unsaturation are also increased in CE fatty acids, indicating further utilization of PUFAs in the absence of FASN activity. As expected, the combination of FASN and HMGCR inhibitors significantly potentiates cell death, observed by stronger reduction in cell growth than either of the single agents, both in androgen-sensitive and castration-resistant models of PCa. Altogether, our data suggests that cholesterol synthesis is a survival mechanism of PCa induced by DNL inhibition, likely to correct for membrane fluidity and energy supply. Finally, statin therapy can be combined with FASN inhibition to suppress PCa growth more efficiently than monotherapy. Citation Format: Caroline Fidalgo Ribeiro, Silvia Daniele Rodrigues, Guilherme Tamarindo, Hubert Pakula, Massimo Loda. De novo lipogenesis and cholesterol synthesis pathways can be simultaneously targeted to induce metabolic synthetic lethality in prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3676.