Targeting the Mevalonate Pathway Suppresses VHL-Deficient CC-RCC through an HIF-Dependent Mechanism

Abstract

Clear cell renal cell carcinoma (CC-RCC) is a devastating disease with limited therapeutic options available for advanced stages. The objective of this study was to investigate HMG-CoA reductase inhibitors, also known as statins, as potential therapeutics for CC-RCC. Importantly, treatment with statins was found to be synthetically lethal with the loss of the von Hippel-Lindau () tumor suppressor gene, which occurs in 90% of CC-RCC driving the disease. This effect has been confirmed in three different CC-RCC cell lines with three different lipophilic statins. Inhibition of mevalonate synthesis by statins causes a profound cytostatic effect at nanomolar concentrations and becomes cytotoxic at low micromolar concentrations in -deficient CC-RCC. The synthetic lethal effect can be fully rescued by both mevalonate and geranylgeranylpyrophosphate, but not by squalene, indicating that the effect is due to disruption of small GTPase isoprenylation and not the inhibition of cholesterol synthesis. Inhibition of Rho and Rho kinase (ROCK) signaling contributes to the synthetic lethality effect, and overactivation of hypoxia-inducible factor signaling resulting from loss is required. Finally, statin treatment is able to inhibit both tumor initiation and progression of subcutaneous 786-OT1-based CC-RCC tumors in mice. Thus, statins represent potential therapeutics for the treatment of -deficient CC-RCC..

Statins as Anticancer Agents in the Era of Precision Medicine

“…Cancer type-specific biomarkers of statin sensitivity may also exist. For example, in clear cell renal cell carcinoma, cells driven by loss of the tumor suppressor von Hippel-Lindau (VHL) (~90% of tumors) were found to be dependent on the MVA pathway for proper RHO and RHO kinase (ROCK) signalling, and were more sensitive to statin treatment compared to VHL wildtype cells (54). Moreover, in multiple myeloma, cancer cells driven by a t (4;14) chromosomal translocation are highly dependent on GGPP synthesis and are more sensitive to statin-induced apoptosis compared to other multiple myeloma subtypes (55).…”

The Mevalonate Pathway, a Metabolic Target in Cancer Therapy

“…Under hypoxic conditions, HIF-1α is stabilized, binds DNA, and regulates the transcription of glycolytic target genes in cancer cells ( 125 , 128 ). Several observations have shown that the MVA pathway can be directly or indirectly modulated under hypoxic conditions, in part, because HMGCR expression is regulated through the transcriptional activity of HIF-1α ( 129 , 130 ). It has been reported that HIF-1α connects pathways for oxygen sensing and feedback regulation of cholesterol synthesis in human fibroblasts by directly inducing the transcription of the INSIG-2 gene.…”

Differential Effects of HIF2α Antagonist and HIF2α Silencing in Renal Cancer and Sensitivity to Repurposed Drugs

“…With the exception of a single plate, which was excluded from the analysis due to a plating error, the correlation between the replicates was good, with an average Pearson's coe cient of 0.920. Taking into account previously published data 23 , the statins simvastatin and uvastatin were further analysed, as well as the squalene monooxygenase inhibitor terbina ne, which blocks cholesterol synthesis while allows the synthesis of non-sterol isoprenoids. We showed that the resistance of 786-0 WT cells to statins was due to HIF2α expression, as silencing HIF2α made the cells more sensitive (Fig.…”

“…Therefore, it is necessary to use a different approach to discover drugs against this malignancy. Statins (small-molecule inhibitors of the 3hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase (HMGR), the rate limiting enzyme of the mevalonate pathway) are reported to be differentially toxic for VHL-defective ccRCC cell lines 23 , suggesting that repurposing well-known and well-characterized drugs could provide a novel therapeutic strategy to target ccRCC combined with PT2385, as statins have long been used to reduce cholesterol levels 24 .…”