Novel p53 reactivators that are synergistic with olaparib for the treatment of gynecologic cancers with mutant p53

IF 5 2区 医学 Q2 Medicine
Lane E. Smith , Jamie L. Padilla , Angelina Licor , Mara P. Steinkamp , Irina V. Lagutina , Yan Guo , Eric J. Devor , Vernon S. Pankratz , Annahita Sallmyr , Olufunmilola M. Oyebamiji , Jun-yong Choe , Geneva L. Williams , Kimberly K. Leslie
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Abstract

Ovarian and endometrial cancers frequently harbor a mutation in the tumor suppressor gene TP53, which occurs in over 90 % of ovarian cancers and in the most aggressive endometrial cancers. The normal tumor suppressive functions of p53 are disrupted, resulting in unregulated cell growth and therapeutic resistance to standard treatments including chemotherapy and PARP inhibitors. Hence, a novel therapeutic strategy is urgently needed for p53 mutant gynecologic cancers, and we propose that converting mutant p53 to a wild type conformation and restoring its tumor suppressive functions has the potential to greatly improve treatment. In this study, we investigated the effects of two purported p53 reactivators, HO-3867 and APR-246, on cell proliferation via half-maximal inhibitory concentration (IC50) analyses using CyQUANT DNA measurements, tumor growth in vivo and gene expression by bulk RNA sequencing in gynecologic cancer cell lines that harbor oncogenic mutations in p53. We also tested these compounds in combination with the PARP inhibitor olaparib. We found that HO-3867 was very effective in inhibiting growth, with IC50 values in the low micromolar range. Importantly, HO-3867 was synergistic with olaparib treatment in five cell lines studied in vitro as well as in vivo in a xenograft model of high grade serous ovarian cancer. RNA sequencing data suggest that HO-3867 is acting through both p53-independent and p53-dependent pathways resulting in inhibition of DNA repair pathways including homologous recombination in p53 mutant cancer cells.
Significance: The development of resistance to PARP inhibitors is a major problem and a cause of treatment failures in advanced gynecologic cancers, and we show that adding a p53 reactivator such as HO-3867 enhances the efficacy of PARP inhibitors in p53-mutant cancer models.
与奥拉帕尼协同作用的新型p53再激活剂用于治疗p53突变的妇科癌症
卵巢癌和子宫内膜癌经常携带肿瘤抑制基因TP53突变,这种突变发生在90%以上的卵巢癌和最具侵袭性的子宫内膜癌中。p53正常的肿瘤抑制功能被破坏,导致细胞生长不受调节,并对包括化疗和PARP抑制剂在内的标准治疗产生耐药性。因此,迫切需要一种新的治疗策略来治疗p53突变型妇科癌症,我们提出将突变型p53转化为野生型构象并恢复其肿瘤抑制功能有可能大大提高治疗效果。在这项研究中,我们研究了两种p53再激活剂HO-3867和APR-246对细胞增殖的影响,通过CyQUANT DNA测量的半最大抑制浓度(IC50)分析,体内肿瘤生长和通过大量RNA测序的p53致癌突变的妇科癌细胞系的基因表达。我们还测试了这些化合物与PARP抑制剂奥拉帕尼的组合。我们发现HO-3867抑制生长非常有效,IC50值在低微摩尔范围内。重要的是,HO-3867在体外和体内高级别浆液性卵巢癌异种移植模型中与奥拉帕尼治疗的五种细胞系中具有协同作用。RNA测序数据表明,HO-3867同时通过p53非依赖型和p53依赖型途径起作用,从而抑制p53突变癌细胞中包括同源重组在内的DNA修复途径。意义:PARP抑制剂耐药性的发展是晚期妇科癌症治疗失败的主要问题和原因,我们发现在p53突变癌症模型中添加p53再激活剂如HO-3867可增强PARP抑制剂的疗效。
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来源期刊
CiteScore
8.40
自引率
2.00%
发文量
314
审稿时长
54 days
期刊介绍: Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.
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