Castrate-resistant prostate cancer response to taxane is determined by an HNF1-dependent apoptosis resistance circuit.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2024-12-17 Epub Date: 2024-12-09 DOI:10.1016/j.xcrm.2024.101868

Ilya S Senatorov, Joel Bowman, Keith H Jansson, Aian Neil Alilin, Brian J Capaldo, Ross Lake, Morgan Riba, Yasmine C Abbey, Crystal Mcknight, Xiaohu Zhang, Sonam Raj, Michael L Beshiri, Paul Shinn, Holly Nguyen, Craig J Thomas, Eva Corey, Kathleen Kelly

{"title":"Castrate-resistant prostate cancer response to taxane is determined by an HNF1-dependent apoptosis resistance circuit.","authors":"Ilya S Senatorov, Joel Bowman, Keith H Jansson, Aian Neil Alilin, Brian J Capaldo, Ross Lake, Morgan Riba, Yasmine C Abbey, Crystal Mcknight, Xiaohu Zhang, Sonam Raj, Michael L Beshiri, Paul Shinn, Holly Nguyen, Craig J Thomas, Eva Corey, Kathleen Kelly","doi":"10.1016/j.xcrm.2024.101868","DOIUrl":null,"url":null,"abstract":"<p><p>Metastatic castrate-resistant prostate cancer (mCRPC) is a genetically and phenotypically heterogeneous cancer where advancements are needed in biomarker discovery and targeted therapy. A critical and often effective component of treatment includes taxanes. We perform a high-throughput screen across a cohort of 30 diverse patient-derived castrate-resistant prostate cancer (CRPC) organoids to a library of 78 drugs. Combining quantitative response measures with transcriptomic analyses demonstrates that HNF1 homeobox A (HNF1A) drives a transcriptional program of taxane resistance, commonly dependent upon cellular inhibitor of apoptosis protein 2 (cIAP2). Monotherapy with cIAP2 inhibitor LCL161 is sufficient to treat HNF1A+ models of mCRPC previously resistant to docetaxel. These data may be useful in future clinical trial designs.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101868"},"PeriodicalIF":11.7000,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722106/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Reports Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.xcrm.2024.101868","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/9 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Metastatic castrate-resistant prostate cancer (mCRPC) is a genetically and phenotypically heterogeneous cancer where advancements are needed in biomarker discovery and targeted therapy. A critical and often effective component of treatment includes taxanes. We perform a high-throughput screen across a cohort of 30 diverse patient-derived castrate-resistant prostate cancer (CRPC) organoids to a library of 78 drugs. Combining quantitative response measures with transcriptomic analyses demonstrates that HNF1 homeobox A (HNF1A) drives a transcriptional program of taxane resistance, commonly dependent upon cellular inhibitor of apoptosis protein 2 (cIAP2). Monotherapy with cIAP2 inhibitor LCL161 is sufficient to treat HNF1A+ models of mCRPC previously resistant to docetaxel. These data may be useful in future clinical trial designs.

查看原文本刊更多论文

去势抵抗性前列腺癌对紫杉烷的反应是由hnf1依赖的细胞凋亡抵抗回路决定的。

转移性去势抵抗性前列腺癌（mCRPC）是一种遗传和表型异质性的癌症，需要在生物标志物发现和靶向治疗方面取得进展。一种关键且通常有效的治疗成分包括紫杉烷。我们对30种不同的患者来源的去势抵抗性前列腺癌（CRPC）类器官进行了高通量筛选，筛选出了78种药物库。结合定量响应测量和转录组学分析表明，HNF1同型框A （HNF1A）驱动紫杉烷抗性的转录程序，通常依赖于细胞凋亡蛋白2抑制剂（cIAP2）。单药cIAP2抑制剂LCL161足以治疗先前对多西他赛耐药的HNF1A+ mCRPC模型。这些数据可能对未来的临床试验设计有用。

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

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.