Department of Pathology, Stony Brook University, Stony Brook, NY, USA.
Cell Death Dis. 2020 Apr 24;11(4):274. doi: 10.1038/s41419-020-2466-4.
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.
错义突变 p53 获得性功能（mutp53 GOF）的一个重要组成部分是稳定的 mutp53 蛋白上调甲羟戊酸途径的能力，这为探索他汀类 HMG-CoA 还原酶抑制剂作为 mutp53 肿瘤的抗癌药物提供了依据。在这项小型探索性研究中，我们报告了他汀类药物治疗表达两种不同 GOF mutp53 等位基因的临床晚期 T 细胞淋巴瘤自发小鼠模型的效果。我们发现，瑞舒伐他汀单药治疗在表达 p53 R248Q DNA 接触突变体的自发 T 淋巴瘤中表现出适度的、p53 等位基因选择性和短暂的抗肿瘤作用，但在表达 p53 R172H 构象突变体的肿瘤中则没有。p53 缺失小鼠也没有受益。他汀类药物体外敏感性不是体内敏感性的强预测因子，而皮下同种异体移植物则是。未来有理由探索他汀类药物联合治疗以提高其抗肿瘤作用，并更好地确定 mutp53 稳定癌症中最敏感的等位基因和肿瘤类型。
