Laboratory of Molecular Carcinogenesis, Division of Cellular & Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore.
Department of Biochemistry, National University of Singapore (NUS), 8 Medical Drive, Singapore 117597, Singapore.
Nat Rev Clin Oncol. 2018 Jan;15(1):13-30. doi: 10.1038/nrclinonc.2017.151. Epub 2017 Sep 26.
TP53, which encodes the tumour-suppressor protein p53, is the most frequently mutated gene across all cancer types. The presence of mutant p53 predisposes to cancer development, promotes the survival of cancer cells, and is associated with ineffective therapeutic responses and unfavourable prognoses. Despite these effects, no drug that abrogates the oncogenic functions of mutant p53 has yet been approved for the treatment of cancer. Current investigational therapeutic strategies are mostly aimed at restoring the wild-type activity of mutant p53, based on the assumption that all p53 mutants are functionally equal. Our increasing knowledge of mutant forms of p53, however, supports the antithetical hypothesis that not all p53 mutants have equivalent cellular effects; hence, a judicious approach to therapeutic targeting of mutant p53 is required. In this Review, we propose a categorization of the major classes of p53 mutants based on their functionality in tumour suppression and response to therapy. The emerging picture is that the mutations across TP53 form a 'rainbow of mutants', with varying degrees of functionality and different pathobiological consequences, necessitating the use of diverse therapeutic strategies to selectively target specific classes of mutation. The utility of this knowledge of TP53 mutations in developing selective therapeutic options, and in facilitating clinical decision-making is discussed.
TP53 基因编码肿瘤抑制蛋白 p53，是所有癌症类型中突变最频繁的基因。突变型 p53 的存在易导致癌症的发生，促进癌细胞的存活，并与无效的治疗反应和不良预后相关。尽管有这些影响，但尚未批准任何一种能消除突变型 p53 致癌功能的药物用于癌症治疗。目前的研究性治疗策略主要基于恢复突变型 p53 的野生型活性，假设所有 p53 突变体在功能上都是平等的。然而，我们对 p53 突变体形式的不断增加的认识支持了相反的假设，即并非所有 p53 突变体都具有等效的细胞效应；因此，需要明智地针对突变型 p53 进行治疗靶向。在这篇综述中，我们根据它们在肿瘤抑制和对治疗的反应中的功能，提出了一种对主要 p53 突变体类别的分类。新兴的观点是，TP53 中的突变形成了一个“突变体彩虹”，具有不同程度的功能和不同的病理生物学后果，需要使用不同的治疗策略来选择性地针对特定类别的突变。讨论了这种对 TP53 突变的认识在开发选择性治疗方案和促进临床决策中的作用。
