Statin as anti-cancer therapy in autochthonous T-lymphomas expressing stabilized gain-of-function mutant p53 proteins

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.

Chaperones and Ubiquitin Ligases Balance Mutant p53 Protein Stability in Esophageal and Other Digestive Cancers

“…Additionally, variables such as the use of lipophilic vs hydrophilic statins, dosage, and dose frequency may substantially alter outcomes. 94 , 95 …”

“…These results emphasize the importance of mutant p53 genotype specificity in the potential efficacy of statin treatment. 95 …”

“… 98 Overall, studies analyzing anticancer effects of statins demonstrate considerable success, and it is worthwhile to continue investigating statin usage in mutant p53–driven cancers, including elucidating factors that affect its efficacy and whether statins may exhibit synergistic effects when combined with chemotherapeutics or other targeted therapies. 95 …”

“…Additionally, variables such as the use of lipophilic vs hydrophilic statins, dosage, and dose frequency may substantially alter outcomes. 94,95 Several studies suggest that statins can play an antitumorigenic role through counteracting mutant p53 stabilization. 41,81,[96][97][98] As previously mentioned, statins interfere with the mevalonate pathway through reducing the production of MVP and downstream products.…”

“…Statins can block HDAC6 activity directly or indirectly via interference in the mevalonate pathway. 95,96 In the latter case, statin-induced reduction of MVP impairs the function of RhoA-GTPases, which usually stimulate HDAC6 activity through cytoskeletal cues. 99 While many studies demonstrate the ability of statins to destabilize mutant p53 and impair growth of p53-driven cancer cells, these are mostly restricted to in vitro systems.…”