Abstract
An important component of missense mutant p53 gain-of-function (mutp53 GOF) activities is the ability of stabilized mutp53 proteins to upregulate the mevalonate pathway, providing a rationale for exploring the statin family of HMG-CoA reductase inhibitors as anticancer agents in mutp53 tumors. In this small exploratory study we report on the effects of statin treatment in autochthonous mouse models of clinically advanced T-cell lymphoma expressing two different GOF mutp53 alleles. We find that Rosuvastatin monotherapy shows a modest, p53 allele-selective and transient anti-tumor effect in autochthonous T-lymphomas expressing the p53 R248Q DNA contact mutant, but not in tumors expressing the p53 R172H conformational mutant. p53 null mice also do not benefit. In vitro statin sensitivity is not a strong predictor for in vivo sensitivity, while subcutaneous allografts are. Future explorations of statins in combination therapies are justified to improve its anti-tumor effects and to better define the most statin-sensitive alleles and tumor types among mutp53-stabilized cancers.
Highlights
Statins have long been suspected to have antitumor activity
Similar results were seen with Atorvastatin
The mevalonate pathway is a central metabolic hub that is essential for cellular cholesterol synthesis, membrane building, and intracellular transport, and as source of biologically active isoprenoids enabling lipid modification of numerous proteins for membrane association and cellular signaling
Summary
Some epidemiological evidence correlates coinciding statin use with reduced mortality from sporadic cancers including colorectal, breast, lung, prostate, and kidney cancers[1,2,3,4,5,6,7,8,9]. This is supported by preclinical studies that show that statins directly inhibit e.g. prostate and pancreatic cancer development and progression in celland animal-based models[2,3,10,11].
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