去势抵抗性前列腺癌对紫杉烷的反应由一个依赖HNF1的抗凋亡回路决定。

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

作者信息

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

机构信息

Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.

Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.

出版信息

Cell Rep Med. 2024 Dec 17;5(12):101868. doi: 10.1016/j.xcrm.2024.101868. Epub 2024 Dec 9.

DOI:10.1016/j.xcrm.2024.101868

PMID:39657662

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11722106/

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.

摘要

转移性去势抵抗性前列腺癌（mCRPC）是一种基因和表型异质性癌症，在生物标志物发现和靶向治疗方面仍需取得进展。治疗的一个关键且通常有效的组成部分包括紫杉烷类药物。我们对30个来自不同患者的去势抵抗性前列腺癌（CRPC）类器官组成的队列进行了针对78种药物文库的高通量筛选。将定量反应测量与转录组分析相结合表明，肝细胞核因子1同源框A（HNF1A）驱动了紫杉烷耐药的转录程序，这通常依赖于细胞凋亡抑制蛋白2（cIAP2）。用cIAP2抑制剂LCL161进行单药治疗足以治疗先前对多西他赛耐药的mCRPC的HNF1A+模型。这些数据可能对未来的临床试验设计有用。