Zhao Dekuang, Tahaney William M, Mazumdar Abhijit, Savage Michelle I, Brown Powel H
Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit Number: 1360, Room Number: CPB6.3468, Houston, TX, 77030, USA.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Cell Mol Life Sci. 2017 Nov;74(22):4171-4187. doi: 10.1007/s00018-017-2575-0. Epub 2017 Jun 22.
The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but also often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with mutated p53 often exhibit specific functional dependencies on secondary genes or pathways to survive, providing alternative targets to indirectly treat p53-mutant cancers. Targeting these genes or pathways, critical for survival in the presence of p53 mutations, holds great promise for cancer treatment. In addition, mutant p53 often exhibits novel gain-of-functions to promote tumor growth and metastasis. Here, we review and discuss strategies targeting mutant p53, with focus on targeting the mutant p53 protein directly, and on the progress of identifying genes and pathways required in p53-mutant cells.
肿瘤抑制因子p53在大约一半的人类癌症中缺失或发生突变。突变型p53不仅丧失了其抗肿瘤转录活性，还常常获得致癌功能以促进肿瘤增殖、侵袭和耐药性。传统策略一直是通过鉴定小分子化合物来直接靶向p53突变体，以清除突变型p53，或恢复其肿瘤抑制功能。越来越多的证据表明，p53发生突变的癌细胞在生存方面往往对二级基因或信号通路表现出特定的功能依赖性，这为间接治疗p53突变型癌症提供了替代靶点。靶向这些在p53突变情况下对生存至关重要的基因或信号通路，在癌症治疗方面具有巨大潜力。此外，突变型p53常常表现出新的功能获得，以促进肿瘤生长和转移。在此，我们综述并讨论靶向突变型p53的策略，重点是直接靶向突变型p53蛋白，以及鉴定p53突变细胞中所需基因和信号通路的进展。
