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
{"title":"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","authors":"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","doi":"10.1016/j.tranon.2025.102522","DOIUrl":null,"url":null,"abstract":"<div><div>Ovarian and endometrial cancers frequently harbor a mutation in the tumor suppressor gene <em>TP53</em>, 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 <em>in vivo</em> 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 <em>in vitro</em> as well as <em>in vivo</em> 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.</div><div><strong>Significance:</strong> 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.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"61 ","pages":"Article 102522"},"PeriodicalIF":5.0000,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Novel p53 reactivators that are synergistic with olaparib for the treatment of gynecologic cancers with mutant p53\",\"authors\":\"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\",\"doi\":\"10.1016/j.tranon.2025.102522\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Ovarian and endometrial cancers frequently harbor a mutation in the tumor suppressor gene <em>TP53</em>, 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 <em>in vivo</em> 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 <em>in vitro</em> as well as <em>in vivo</em> 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.</div><div><strong>Significance:</strong> 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.</div></div>\",\"PeriodicalId\":48975,\"journal\":{\"name\":\"Translational Oncology\",\"volume\":\"61 \",\"pages\":\"Article 102522\"},\"PeriodicalIF\":5.0000,\"publicationDate\":\"2025-09-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Translational Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1936523325002530\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Translational Oncology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1936523325002530","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Medicine","Score":null,"Total":0}
Novel p53 reactivators that are synergistic with olaparib for the treatment of gynecologic cancers with mutant p53
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.
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.