Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy

SIMPLE SUMMARY: For tumors to initiate and sustain rapid growth, they need to alter their metabolic reprograming to support this growth. While many oncogenes upregulate metabolic pathways in cancer, here, we focus on how mutant p53 interacts with the mevalonate pathway (MVA) and functions as a continual on switch, causing tumor cells to grow uncontrollably. The relationship of mutant p53 and the MVA pathway in promoting tumorigenesis and the pleiotropic effects within the tumor microenvironment as a result of MVA pathway upregulation are discussed in this review. Many individuals are prescribed a statin drug to decrease their circulating cholesterol levels by blocking the MVA pathway. Several studies have suggested the potential of repurposing statins to treat various cancers, since tumor cells upregulate and rely substantially on the MVA pathway. We evaluate previous studies on statins and cancer incidence and patient mortality, as well as future research to optimize the use of statins as a cancer therapy. ABSTRACT: Tumor cells have the ability to co-opt multiple metabolic pathways, enhance glucose uptake and utilize aerobic glycolysis to promote tumorigenesis, which are characteristics constituting an emerging hallmark of cancer. Mutated tumor suppressor and proto-oncogenes are frequently responsible for enhanced metabolic pathway signaling. The link between mutant p53 and the mevalonate (MVA) pathway has been implicated in the advancement of various malignancies, with tumor cells relying heavily on increased MVA signaling to fuel their rapid growth, metastatic spread and development of therapy resistance. Statin drugs inhibit HMG-CoA reductase, the pathway’s rate-limiting enzyme, and as such, have long been studied as a potential anti-cancer therapy. However, whether statins provide additional anti-cancer properties is worthy of debate. Here, we examine retrospective, prospective and pre-clinical studies involving the use of statins in various cancer types, as well as potential issues with statins’ lack of efficacy observed in clinical trials and future considerations for upcoming clinical trials.