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异位 JAK-STAT 激活使细胞向干细胞样和多能性状态转变，从而赋予对 AR 靶向治疗的抗性。

Ectopic JAK-STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance.

机构信息

Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA.

Quantitative Biomedical Research Center, Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX, USA.

出版信息

Nat Cancer. 2022 Sep;3(9):1071-1087. doi: 10.1038/s43018-022-00431-9. Epub 2022 Sep 5.

DOI:10.1038/s43018-022-00431-9
PMID:36065066
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9499870/
Abstract

Emerging evidence indicates that various cancers can gain resistance to targeted therapies by acquiring lineage plasticity. Although various genomic and transcriptomic aberrations correlate with lineage plasticity, the molecular mechanisms enabling the acquisition of lineage plasticity have not been fully elucidated. We reveal that Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is a crucial executor in promoting lineage plasticity-driven androgen receptor (AR)-targeted therapy resistance in prostate cancer. Importantly, ectopic JAK-STAT activation is specifically required for the resistance of stem-like subclones expressing multilineage transcriptional programs but not subclones exclusively expressing the neuroendocrine-like lineage program. Both genetic and pharmaceutical inhibition of JAK-STAT signaling resensitizes resistant tumors to AR-targeted therapy. Together, these results suggest that JAK-STAT are compelling therapeutic targets for overcoming lineage plasticity-driven AR-targeted therapy resistance.

摘要

新出现的证据表明，各种癌症可以通过获得谱系可塑性获得对靶向治疗的耐药性。虽然各种基因组和转录组异常与谱系可塑性相关，但使谱系可塑性获得的分子机制尚未完全阐明。我们揭示了 Janus 激酶 (JAK)-信号转导子和转录激活子 (STAT) 信号是促进前列腺癌中由谱系可塑性驱动的雄激素受体 (AR)-靶向治疗耐药性的关键执行者。重要的是，异位 JAK-STAT 激活对于表达多谱系转录程序的干细胞样亚克隆的耐药性是特异性需要的，但对于仅表达神经内分泌样谱系程序的亚克隆则不需要。JAK-STAT 信号的遗传和药物抑制均可使耐药肿瘤对 AR 靶向治疗重新敏感。总之，这些结果表明，JAK-STAT 是克服由谱系可塑性驱动的 AR 靶向治疗耐药性的有吸引力的治疗靶点。

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