Novel aspects of mevalonate pathway inhibitors as antitumor agents
Cet article passe en revue les perspectives offertes par des inhibiteurs de la voie de signalisation du mévalonate pour le traitement des cancers
The mevalonate pathway for cholesterol biosynthesis and protein prenylation has been implicated in various aspects of tumor development and progression. Certain classes of drugs, such as the statins and bisphosphonates, inhibit mevalonate metabolism and have therefore also been tested as antitumor agents. This concept is strongly supported by the recent finding that mutant p53, which is present in more than half of all human cancers, can significantly upregulate mevalonate metabolism and protein prenylation in carcinoma cells. First evidence that mevalonate pathway inhibitors may have the potential to reverse the malignant phenotype has already been obtained. Moreover, recently discovered immunomodulatory properties of statins and bisphosphonates may also contribute to their known anticancer effects. Drug-induced inhibition of protein prenylation may induce sequential cellular stress responses including the unfolded protein response and autophagy, which eventually translate into inflammasome-dependent and caspase-1-mediated activation of innate immunity. The present review focuses on these novel capabilities of mevalonate pathway inhibitors to beneficially affect tumor biology as well as to contribute to tumor immune surveillance.