对高危神经母细胞瘤联合抑制 BCL-2 和 MCL-1 的临床前评估。

Lindy Vernooij , Alvin Kamili , Kimberley Ober , Jennemiek van Arkel , Lina Lankhorst , Enya Vermeulen , Hanin Al-Khakany , Gabor Tax , Marlinde L. van den Boogaard , Jamie I. Fletcher , Selma Eising , Jan J. Molenaar , M. Emmy M. Dolman
{"title":"对高危神经母细胞瘤联合抑制 BCL-2 和 MCL-1 的临床前评估。","authors":"Lindy Vernooij ,&nbsp;Alvin Kamili ,&nbsp;Kimberley Ober ,&nbsp;Jennemiek van Arkel ,&nbsp;Lina Lankhorst ,&nbsp;Enya Vermeulen ,&nbsp;Hanin Al-Khakany ,&nbsp;Gabor Tax ,&nbsp;Marlinde L. van den Boogaard ,&nbsp;Jamie I. Fletcher ,&nbsp;Selma Eising ,&nbsp;Jan J. Molenaar ,&nbsp;M. Emmy M. Dolman","doi":"10.1016/j.ejcped.2024.100168","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Neuroblastoma is the most common extracranial pediatric solid malignancy with high-risk patients showing survival rates less than 50 %. These tumors frequently escape apoptosis through upregulation of the anti-apoptotic protein BCL-2. Unfortunately, monotherapy with the BCL-2 inhibitor venetoclax leads to therapy-induced resistance mediated by upregulation of MCL-1, thereby indicating that tumors could be responsive to dual inhibition of BCL-2 and MCL-1.</p></div><div><h3>Methods</h3><p>In vitro efficacy of venetoclax and multiple MCL-1 inhibitors (MIK665, S63845, AMG-176, AZD-5991) was studied in neuroblastoma cell lines with BCL-2 and/or MCL-1 dependency. Synergy assays were performed to identify the MCL-1 inhibitor with best performance in combination with venetoclax, followed by examining if dual BCL-2 and MCL-1 inhibition protects against resistance. Lastly, the combination was analyzed in two patient-derived xenograft (PDX) models.</p></div><div><h3>Results</h3><p>Venetoclax showed highest efficacy in neuroblastoma cell lines with high <em>BCL-2 mRNA</em> expression, BCL-2 protein levels or BIM:BCL-2 complex formation, while MCL-1 inhibitor efficacy was best correlated with BIM:MCL-1 complex levels. Most promising anti-tumor effects were observed following combination therapy with venetoclax and MIK665. Targeting BCL-2 and MCL-1 led to strong synergy and efficacy at low concentrations, induced apoptosis and prevented resistance. PDX validation studies combining venetoclax with MIK665 showed improved responses compared to monotherapies.</p></div><div><h3>Conclusion</h3><p>Dual inhibition of BCL-2 and MCL-1 in neuroblastoma cells showed highly efficacious and synergistic responses in vitro, but only led to mild additive effects in vivo. Hence, better understanding of in vivo efficacy and side effects of this combination treatment are warranted prior to clinical translation.</p></div>","PeriodicalId":94314,"journal":{"name":"EJC paediatric oncology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772610X24000278/pdfft?md5=3225d22e4f1561488932aee2da1837c1&pid=1-s2.0-S2772610X24000278-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Preclinical assessment of combined BCL-2 and MCL-1 inhibition in high-risk neuroblastoma\",\"authors\":\"Lindy Vernooij ,&nbsp;Alvin Kamili ,&nbsp;Kimberley Ober ,&nbsp;Jennemiek van Arkel ,&nbsp;Lina Lankhorst ,&nbsp;Enya Vermeulen ,&nbsp;Hanin Al-Khakany ,&nbsp;Gabor Tax ,&nbsp;Marlinde L. van den Boogaard ,&nbsp;Jamie I. Fletcher ,&nbsp;Selma Eising ,&nbsp;Jan J. Molenaar ,&nbsp;M. Emmy M. Dolman\",\"doi\":\"10.1016/j.ejcped.2024.100168\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>Neuroblastoma is the most common extracranial pediatric solid malignancy with high-risk patients showing survival rates less than 50 %. These tumors frequently escape apoptosis through upregulation of the anti-apoptotic protein BCL-2. Unfortunately, monotherapy with the BCL-2 inhibitor venetoclax leads to therapy-induced resistance mediated by upregulation of MCL-1, thereby indicating that tumors could be responsive to dual inhibition of BCL-2 and MCL-1.</p></div><div><h3>Methods</h3><p>In vitro efficacy of venetoclax and multiple MCL-1 inhibitors (MIK665, S63845, AMG-176, AZD-5991) was studied in neuroblastoma cell lines with BCL-2 and/or MCL-1 dependency. Synergy assays were performed to identify the MCL-1 inhibitor with best performance in combination with venetoclax, followed by examining if dual BCL-2 and MCL-1 inhibition protects against resistance. Lastly, the combination was analyzed in two patient-derived xenograft (PDX) models.</p></div><div><h3>Results</h3><p>Venetoclax showed highest efficacy in neuroblastoma cell lines with high <em>BCL-2 mRNA</em> expression, BCL-2 protein levels or BIM:BCL-2 complex formation, while MCL-1 inhibitor efficacy was best correlated with BIM:MCL-1 complex levels. Most promising anti-tumor effects were observed following combination therapy with venetoclax and MIK665. Targeting BCL-2 and MCL-1 led to strong synergy and efficacy at low concentrations, induced apoptosis and prevented resistance. PDX validation studies combining venetoclax with MIK665 showed improved responses compared to monotherapies.</p></div><div><h3>Conclusion</h3><p>Dual inhibition of BCL-2 and MCL-1 in neuroblastoma cells showed highly efficacious and synergistic responses in vitro, but only led to mild additive effects in vivo. Hence, better understanding of in vivo efficacy and side effects of this combination treatment are warranted prior to clinical translation.</p></div>\",\"PeriodicalId\":94314,\"journal\":{\"name\":\"EJC paediatric oncology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2772610X24000278/pdfft?md5=3225d22e4f1561488932aee2da1837c1&pid=1-s2.0-S2772610X24000278-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"EJC paediatric oncology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2772610X24000278\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"EJC paediatric oncology","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2772610X24000278","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

背景神经母细胞瘤是最常见的颅外儿科实体瘤,高危患者的存活率不到50%。这些肿瘤经常通过上调抗凋亡蛋白 BCL-2 逃避凋亡。方法在具有 BCL-2 和/或 MCL-1 依赖性的神经母细胞瘤细胞系中研究了 Venetoclax 和多种 MCL-1 抑制剂(MIK665、S63845、AMG-176、AZD-5991)的体外疗效。研究人员进行了协同作用试验,以确定与 Venetoclax 联用效果最佳的 MCL-1 抑制剂,随后研究了 BCL-2 和 MCL-1 双抑制是否能防止耐药性。结果Venetoclax在具有高BCL-2 mRNA表达、BCL-2蛋白水平或BIM:BCL-2复合物形成的神经母细胞瘤细胞系中显示出最高的疗效,而MCL-1抑制剂的疗效与BIM:MCL-1复合物水平的相关性最好。venetoclax和MIK665联合疗法的抗肿瘤效果最为理想。以BCL-2和MCL-1为靶点可产生很强的协同作用,在低浓度下就能产生疗效,诱导细胞凋亡并防止耐药性。结论神经母细胞瘤细胞中BCL-2和MCL-1的双重抑制在体外显示出高效的协同反应,但在体内仅产生轻微的相加效应。因此,在进行临床转化之前,需要更好地了解这种联合疗法的体内疗效和副作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Preclinical assessment of combined BCL-2 and MCL-1 inhibition in high-risk neuroblastoma

Background

Neuroblastoma is the most common extracranial pediatric solid malignancy with high-risk patients showing survival rates less than 50 %. These tumors frequently escape apoptosis through upregulation of the anti-apoptotic protein BCL-2. Unfortunately, monotherapy with the BCL-2 inhibitor venetoclax leads to therapy-induced resistance mediated by upregulation of MCL-1, thereby indicating that tumors could be responsive to dual inhibition of BCL-2 and MCL-1.

Methods

In vitro efficacy of venetoclax and multiple MCL-1 inhibitors (MIK665, S63845, AMG-176, AZD-5991) was studied in neuroblastoma cell lines with BCL-2 and/or MCL-1 dependency. Synergy assays were performed to identify the MCL-1 inhibitor with best performance in combination with venetoclax, followed by examining if dual BCL-2 and MCL-1 inhibition protects against resistance. Lastly, the combination was analyzed in two patient-derived xenograft (PDX) models.

Results

Venetoclax showed highest efficacy in neuroblastoma cell lines with high BCL-2 mRNA expression, BCL-2 protein levels or BIM:BCL-2 complex formation, while MCL-1 inhibitor efficacy was best correlated with BIM:MCL-1 complex levels. Most promising anti-tumor effects were observed following combination therapy with venetoclax and MIK665. Targeting BCL-2 and MCL-1 led to strong synergy and efficacy at low concentrations, induced apoptosis and prevented resistance. PDX validation studies combining venetoclax with MIK665 showed improved responses compared to monotherapies.

Conclusion

Dual inhibition of BCL-2 and MCL-1 in neuroblastoma cells showed highly efficacious and synergistic responses in vitro, but only led to mild additive effects in vivo. Hence, better understanding of in vivo efficacy and side effects of this combination treatment are warranted prior to clinical translation.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
0.20
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信