Targeting mutant p53 for cancer therapy: direct and indirect strategies.
Targeting mutant p53 for cancer therapy: direct and indirect strategies.
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DOI：
10.1186/s13045-021-01169-0
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发表时间：
2021-09-28
影响因子：
28.5
通讯作者：
Chen M
中科院分区：
文献类型：
--
作者：
Hu J;Cao J;Topatana W;Juengpanich S;Li S;Zhang B;Shen J;Cai L;Cai X;Chen M
TP 53是一种重要的肿瘤抑制基因，在超过一半的人类癌症中发生突变。TP 53的突变不仅损害其抗肿瘤活性，而且赋予突变型p53蛋白致癌特性。p53靶向治疗方法始于鉴定能够恢复/重新激活野生型p53功能或消除突变型p53的化合物。直接靶向突变型p53的治疗是极其结构和药物物种依赖性的。由于野生型p53的突变，通常由野生型p53维持的多种存活途径被破坏，需要激活补偿基因或途径来促进癌细胞存活。此外，由于突变型p53的致癌功能有助于癌症增殖和转移，靶向p53突变改变的信号通路似乎是一个有吸引力的策略。合成致死性意味着，虽然在具有合成致死相互作用的两个基因中，单独破坏任一基因是允许的，但两个基因的完全破坏导致细胞死亡。因此，不是直接靶向p53，而是利用突变型p53合成致死基因可以提供额外的治疗益处。此外，对非编码RNA功能的研究进展表明，破坏非编码RNA网络具有良好的抗肿瘤作用，支持靶向非编码RNA可能在p53突变的癌症中具有潜在的合成致死作用的假设。本综述的目的是讨论突变型p53癌症的治疗方法，重点是直接靶向突变型p53，恢复野生型功能，并利用突变型p53的合成致死相互作用。此外，将讨论非编码RNA作为突变型p53的合成致死靶点的可能性。
TP53 is a critical tumor-suppressor gene that is mutated in more than half of all human cancers. Mutations in TP53 not only impair its antitumor activity, but also confer mutant p53 protein oncogenic properties. The p53-targeted therapy approach began with the identification of compounds capable of restoring/reactivating wild-type p53 functions or eliminating mutant p53. Treatments that directly target mutant p53 are extremely structure and drug-species-dependent. Due to the mutation of wild-type p53, multiple survival pathways that are normally maintained by wild-type p53 are disrupted, necessitating the activation of compensatory genes or pathways to promote cancer cell survival. Additionally, because the oncogenic functions of mutant p53 contribute to cancer proliferation and metastasis, targeting the signaling pathways altered by p53 mutation appears to be an attractive strategy. Synthetic lethality implies that while disruption of either gene alone is permissible among two genes with synthetic lethal interactions, complete disruption of both genes results in cell death. Thus, rather than directly targeting p53, exploiting mutant p53 synthetic lethal genes may provide additional therapeutic benefits. Additionally, research progress on the functions of noncoding RNAs has made it clear that disrupting noncoding RNA networks has a favorable antitumor effect, supporting the hypothesis that targeting noncoding RNAs may have potential synthetic lethal effects in cancers with p53 mutations. The purpose of this review is to discuss treatments for cancers with mutant p53 that focus on directly targeting mutant p53, restoring wild-type functions, and exploiting synthetic lethal interactions with mutant p53. Additionally, the possibility of noncoding RNAs acting as synthetic lethal targets for mutant p53 will be discussed.
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DOI：
10.1093/database/bat034
发表时间：
2013
期刊：
Database : the journal of biological databases and curation
影响因子：
--
作者：
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通讯作者：
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影响因子：
11.4
作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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DOI：
10.1158/1078-0432.ccr-11-0650
发表时间：
2011-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
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通讯作者：
Meyn RE
DOI：
10.1002/wrna.1410
发表时间：
2017-05
期刊：
Wiley interdisciplinary reviews. RNA
影响因子：
--
作者：
Chaudhary R;Lal A
通讯作者：
Lal A