AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients With MTAP-Deleted Cancers.

IF 29.7 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2024-09-16 DOI:10.1158/2159-8290.CD-24-0887

Brian Belmontes, Katherine K Slemmons, Chun Su, Siyuan Liu, Antonia N Policheni, Jodi Moriguchi, Hong Tan, Fang Xie, Daniel Andrew Aiello, Yajing Yang, Raul Lazaro, Famke Aeffner, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Mikkel Vestergaard, Sanne Cowland, Jan Andersson, Ian Sarvary, Qing Chen, Pooja Sharma, Patricia Lopez, Nuria Tamayo, Liping H Pettus, Sudipa Ghimire-Rijal, Susmith Mukund, Jennifer R Allen, Jason DeVoss, Angela Coxon, Jordi Rodon, Francois Ghiringhelli, Nicolas Penel, Hans Prenen, Sanne Glad, Chen-Hua Chuang, Kiana Keyvanjah, Danielle M Townsley, John R Butler, Matthew P Bourbeau, Sean Caenepeel, Paul E Hughes

{"title":"AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients With MTAP-Deleted Cancers.","authors":"Brian Belmontes, Katherine K Slemmons, Chun Su, Siyuan Liu, Antonia N Policheni, Jodi Moriguchi, Hong Tan, Fang Xie, Daniel Andrew Aiello, Yajing Yang, Raul Lazaro, Famke Aeffner, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Mikkel Vestergaard, Sanne Cowland, Jan Andersson, Ian Sarvary, Qing Chen, Pooja Sharma, Patricia Lopez, Nuria Tamayo, Liping H Pettus, Sudipa Ghimire-Rijal, Susmith Mukund, Jennifer R Allen, Jason DeVoss, Angela Coxon, Jordi Rodon, Francois Ghiringhelli, Nicolas Penel, Hans Prenen, Sanne Glad, Chen-Hua Chuang, Kiana Keyvanjah, Danielle M Townsley, John R Butler, Matthew P Bourbeau, Sean Caenepeel, Paul E Hughes","doi":"10.1158/2159-8290.CD-24-0887","DOIUrl":null,"url":null,"abstract":"<p><p>One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on PRMT5 in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust antitumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7000,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2159-8290.CD-24-0887","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on PRMT5 in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust antitumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.

查看原文本刊更多论文

AMG 193 是一种处于临床阶段的 MTA-Cooperative PRMT5 抑制剂，在临床前和 MTAP 缺失的癌症患者中具有抗肿瘤活性。

在多个功能基因组筛选中观察到的最强大的合成致死相互作用之一是 MTAP 缺失的癌细胞对 PRMT5 的依赖性。我们报告发现了处于临床阶段的 MTA 协同 PRMT5 抑制剂 AMG 193，它在 MTA 存在的情况下优先结合 PRMT5，并在多个癌系的 MTAP 缺失细胞中具有强大的生化和细胞活性。在体外，抑制 PRMT5 可诱导 MTAP 缺失细胞的 DNA 损伤、细胞周期停滞和异常替代 mRNA 剪接。在人类细胞系和患者来源的异种移植模型中，AMG 193 可诱导强大的抗肿瘤活性，而且耐受性良好，对正常造血细胞系没有影响。AMG 193 在体外可与化疗或 KRAS G12C 抑制剂 sotorasib 协同增效，在体内联合治疗可显著抑制肿瘤生长。AMG 193 正在显示出良好的临床活性，包括正在进行的一项 1 / 2 期研究中证实的 MTAP 缺失实体瘤患者的部分应答。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.