Targeting the Mevalonate Pathway in Cancer

Juarez, Dennis; Fruman, David A.

doi:10.1016/j.trecan.2020.11.008

Cited by 82 publications

(54 citation statements)

References 138 publications

(175 reference statements)

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“…3) flux, which is an absolute requirement for all cells, is increased in carcinogenic lesions and is a general feature of cancer [137]. This increased demand for mevalonate is a hallmark of tumorigenesis, and the increased availability of mevalonate pathway intermediates leads to adaptive changes that promote the adaptability of tumor cells [138]. A central motivation for targeting the mevalonate pathway is that selective and well-tolerated inhibitors already exist.…”

Section: Liver Cancermentioning

confidence: 99%

Statins: a repurposed drug to fight cancer

Jiang

et al. 2021

J Exp Clin Cancer Res

220

142

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As competitive HMG-CoA reductase (HMGCR) inhibitors, statins not only reduce cholesterol and improve cardiovascular risk, but also exhibit pleiotropic effects that are independent of their lipid-lowering effects. Among them, the anti-cancer properties of statins have attracted much attention and indicated the potential of statins as repurposed drugs for the treatment of cancer. A large number of clinical and epidemiological studies have described the anticancer properties of statins, but the evidence for anticancer effectiveness of statins is inconsistent. It may be that certain molecular subtypes of cancer are more vulnerable to statin therapy than others. Whether statins have clinical anticancer effects is still an active area of research. Statins appear to enhance the efficacy and address the shortcomings associated with conventional cancer treatments, suggesting that statins should be considered in the context of combined therapies for cancer. Here, we present a comprehensive review of the potential of statins in anti-cancer treatments. We discuss the current understanding of the mechanisms underlying the anti-cancer properties of statins and their effects on different malignancies. We also provide recommendations for the design of future well-designed clinical trials of the anti-cancer efficacy of statins.

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Section: Liver Cancermentioning

confidence: 99%

Statins: a repurposed drug to fight cancer

Jiang

et al. 2021

J Exp Clin Cancer Res

220

142

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“…Considering that PD-L1-suppressive small molecules, such as niclosamide and regorafenib, have shown benefits against the efficacy of the PD-1/PD-L1 immune checkpoint blockade in NSCLC and melanoma [ 42 , 43 ], we hypothesized that statins could also be used for combination cancer therapy with immune checkpoint blockades. In addition, increased evidence has shown that statins suppress cancer cell growth in vitro and in vivo [ 44 ]. PD-L1 promotes cancer cell growth and silencing of PD-L1 by using short hairpin RNA (shRNA)-attenuated cancer cell growth in vitro and in vivo in both NSCLC and hepatocellular carcinoma (HCC) [ 45 , 46 ].…”

Section: Resultsmentioning

confidence: 99%

Statins Decrease Programmed Death-Ligand 1 (PD-L1) by Inhibiting AKT and β-Catenin Signaling

Lim

Lee

et al. 2021

Cells

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Retrospective observational studies have reported that statins improve clinical outcomes in patients previously treated with programmed cell death protein 1 (PD-1)-targeting monoclonal antibodies for malignant pleural mesothelioma (MPM) and advanced non-small cell lung cancer (NSCLC). In multiple mouse cancer models, de novo synthesis of mevalonate and cholesterol inhibitors was found to synergize with anti-PD-1 antibody therapy. In the present study, we investigated whether statins affect programmed death-ligand 1 (PD-L1) expression in cancer cells. Four statins, namely simvastatin, atorvastatin, lovastatin, and fluvastatin, decreased PD-L1 expression in melanoma and lung cancer cells. In addition, we found that AKT and β-catenin signaling involved PD-L1 suppression by statins. Our cellular and molecular studies provide inspiring evidence for extending the clinical evaluation of statins for use in combination with immune checkpoint inhibitor-based cancer therapy.

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“…Upregulation of hepatic endothelial KLF2-derived gene expression by statins confers vasoprotection and inactivates stellate cells, reinforcing the therapeutic potential of these drugs for treating liver disease and endothelial dysfunction [5]. In addition, the mevalonate pathway may also be important in the development of cancer [6,7].…”

Section: Introductionmentioning

confidence: 99%

Cardiac‐specific deletion of FDPS induces cardiac remodeling and dysfunction by enhancing the activity of small GTP‐binding proteins

Wang

Zhang

Chen

et al. 2021

The Journal of Pathology

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The mevalonate pathway is essential for cholesterol biosynthesis. Previous studies have suggested that the key enzyme in this pathway, farnesyl diphosphate synthase (FDPS), regulates the cardiovascular system. We used human samples and mice that were deficient in cardiac FDPS (c-Fdps À/À mice) to investigate the role of FDPS in cardiac homeostasis. Cardiac function was assessed using echocardiography. Left ventricles were examined and tested for histological and molecular markers of cardiac remodeling. Our results showed that FDPS levels were downregulated in samples from patients with cardiomyopathy. Furthermore, c-Fdps À/À mice exhibited cardiac remodeling and dysfunction. This dysfunction was associated with abnormal activation of Ras and Rheb, which may be due to the accumulation of geranyl pyrophosphate. Activation of Ras and Rheb stimulated downstream mTOR and ERK pathways. Moreover, administration of farnesyltransferase inhibitors attenuated cardiac remodeling and dysfunction in c-Fdps À/À mice. These results indicate that FDPS plays an important role in cardiac homeostasis. Deletion of FDPS stimulates the downstream mTOR and ERK signaling pathways, resulting in cardiac remodeling and dysfunction.

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Targeting the Mevalonate Pathway in Cancer

Cited by 82 publications

References 138 publications

Statins: a repurposed drug to fight cancer

Statins: a repurposed drug to fight cancer

Statins Decrease Programmed Death-Ligand 1 (PD-L1) by Inhibiting AKT and β-Catenin Signaling

Cardiac‐specific deletion of FDPS induces cardiac remodeling and dysfunction by enhancing the activity of small GTP‐binding proteins

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