Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Signal Transduct Target Ther. 2023 Mar 1;8(1):92. doi: 10.1038/s41392-023-01347-1.
The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the "guardian of the genome". Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an "undruggable" target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.
抑癌基因 TP53 是人类癌症中最常发生改变的基因，也是肿瘤学研究的主要焦点。p53 蛋白是一种转录因子，可以激活多个靶基因的表达，在调节细胞周期、细胞凋亡和基因组稳定性方面发挥着关键作用，被广泛认为是“基因组的守护者”。越来越多的证据表明，p53 还可以调节细胞代谢、铁死亡、肿瘤微环境、自噬等，所有这些都有助于肿瘤抑制。TP53 中的突变不仅损害了其肿瘤抑制功能，而且赋予了 p53 突变体致癌特性。由于 p53 在大多数恶性肿瘤中发生突变和失活，因此它一直是开发新型抗癌药物的非常有吸引力的靶标。然而，直到最近，p53 被认为是一个“不可成药”的靶标，针对 p53 的靶向治疗几乎没有取得进展。在这里，我们系统地综述了 p53 信号通路的多种分子机制以及 TP53 突变如何影响肿瘤进展。我们还讨论了 p53 蛋白的关键结构特征及其被致癌突变所失活的方式。此外，我们还回顾了在 p53 靶向治疗方面所做的努力，并讨论了在临床开发中所遇到的挑战。
