Division of Cellular & Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore.
Houston Methodist Cancer Center, 6445 Main St, Houston, TX, 77030, USA.
Oncogene. 2019 May;38(18):3415-3427. doi: 10.1038/s41388-018-0652-y. Epub 2019 Jan 14.
Mutations in Tp53 compromise therapeutic response, due either to the dominant-negative effect over the functional wild-type allele; or as a result of the survival advantage conferred by mutant p53 to which cancer cells become addicted. Thus, targeting mutant p53 represents an effective therapeutic strategy to treat over half of all cancers. We have therefore generated a series of small-interfering-RNAs, capable of targeting four p53 hot-spot mutants which represent ~20% of all p53 mutations. These mutant-p53-specific siRNAs (MupSi) are highly specific in silencing the expression of the intended mutants without affecting wild-type p53. Functionally, these MupSis induce cell death by abrogating both the addiction to mutant p53 and the dominant-negative effect; and retard tumor growth in xenografts when administered in a therapeutic setting. These data together demonstrate the possibility of targeting mutant p53 specifically to improve clinical outcome.
突变的 TP53 会影响治疗反应，要么是因为功能正常的野生型等位基因的显性负效应；要么是因为突变型 p53 赋予了癌细胞生存优势，使它们对此产生了依赖。因此，针对突变型 p53 代表了一种有效的治疗策略，可以治疗超过一半的所有癌症。因此，我们生成了一系列小干扰 RNA，可以靶向四个 p53 热点突变，这些突变约占所有 p53 突变的 20%。这些针对突变型 p53 的特异性 siRNA（MupSi）在沉默预期突变体的表达方面具有高度特异性，而不影响野生型 p53。从功能上讲，这些 MupSi 通过消除对突变型 p53 的依赖和显性负效应，诱导细胞死亡；并在治疗性给药时减缓异种移植物中的肿瘤生长。这些数据共同证明了靶向突变型 p53 以改善临床结果的可能性。
