PO.ET06.04 · 实验与分子治疗
PM54靶向多种癌症类型中的致癌转录网络
PM54 targets oncogenic transcriptional networks across multiple cancer types
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：PM54是一种源自lurbinectedin的合成ecteinascidin类似物，它结合富含GC的启动子区域以阻断转录、诱导DNA双链断裂，并触发S期阻滞及凋亡。我们旨在界定PM54在不同肿瘤类型中的转录机制，并识别与更高敏感性相关的转录组特征。
方法：在代表六种肿瘤类型的32株癌细胞系（12株小细胞肺癌[SCLC]、8株胃癌、6株前列腺癌、4株乳腺癌、1株卵巢癌及1株黑色素瘤）中，于急性PM54暴露（50 nM，6小时）后进行全面的转录组学分析（RNA-seq）。采用层次聚类、差异表达、GSEA及GO分析来界定时序性转录反应簇。体内验证在四种CDX模型（SCLC DMS-53、卵巢癌A2780、黑色素瘤WM-266-4及TNBC MDA-MB-231）中于单次PM54给药后进行，并在第7天进行RNA-seq。
结果：PM54在所有模型中诱导了快速、广泛的转录抑制，每系有超过2,000个下调基因，以及一个由1,170个共同受抑制基因组成的保守核心（相比之下共同诱导的基因为226个）。受抑制的程序包括细胞周期、RNA Pol II转录、染色质组织、DNA修复及MYC靶点；早期上调的特征涉及代谢、PARP信号传导及应激反应。基于PM54转录效应的无监督聚类识别出一个“预激”应答簇（其特征为高基线转录及治疗后快速的转录关闭）和一个“适应性”应答簇。有趣的是，所有三株POU2F3 SCLC系及前列腺癌模型均归入预激应答簇。与此一致，体内转录组学分析重现了这些簇，表现出增强的转录抑制、MYC/mTOR信号传导抑制，以及预激应答者（卵巢癌、黑色素瘤及SCLC分别为+192%、+345%和+412%）相比适应性应答者（乳腺癌为+185%，胃癌为+240%）显著改善的生存结局。
结论：PM54快速抑制增殖性/MYC驱动的程序，并引发适应性的代谢/免疫反应。基线转录状态可预测反应，并可能指导患者选择及联合策略。
查看英文原文 English abstract
Background: PM54, a synthetic ecteinascidin analog derived from lurbinectedin, binds GC-rich promoter regions to block transcription, induce DNA double-strand breaks, and trigger S-phase arrest and apoptosis. We aimed to define PM54 transcriptional mechanisms across tumor types and to identify transcriptomic features associated with heightened sensitivity.
Methods: Comprehensive transcriptomic profiling (RNA-seq) was performed following acute PM54 exposure (50 nM, 6 h) in a panel of 32 cancer cell lines representing six tumor types: 12 small-cell lung cancers (SCLC), 8 gastric cancers, 6 prostate cancers, 4 breast cancers, 1 ovarian cancer, and 1 melanoma. Hierarchical clustering, differential expression, GSEA, and GO analyses were used to define temporal transcriptional response clusters. In vivo validation was conducted in four CDX models (SCLC DMS-53, ovarian A2780, melanoma WM-266-4, and TNBC MDA-MB-231) after a single PM54 dose, with RNA-seq performed on day 7.
Results: PM54 induced a rapid, broad transcriptional repression in all models, with >2,000 downregulated genes per line and a conserved core of 1,170 commonly repressed genes (versus 226 commonly induced). Repressed programs included cell cycle, RNA Pol II transcription, chromatin organization, DNA repair and MYC targets; early upregulated signatures implicated metabolism, PARP signaling and stress responses. Unsupervised clustering based on PM54 transcriptional effect identified a “primed” responder cluster (characterized by high baseline transcription and rapid transcriptional shutdown after treatment) and an “adaptive” responder cluster. Curiously, all three POU2F3 SCLC lines and prostate cancer models were into the primed responder cluster. Consistently, in vivo transcriptomic analyses recapitulated these clusters, demonstrating enhanced transcriptional repression, MYC/mTOR signaling suppression, and markedly improved survival outcomes in primed (+192%, +345% and +412% in ovarian, melanoma and SCLC, respectively) compared to adaptive responders (+185% in breast cancer and +240% in gastric cancer).
Conclusions: PM54 rapidly suppresses proliferative/MYC-driven programs and elicits adaptive metabolic/immune responses. Baseline transcriptional state predicts response and may guide patient selection and combination strategies.
利益披露 Disclosure
I. Fernández-Miranda,
Yes Employment, Stock, Stock Option.
J. Robles,
Yes Employment, Stock Option.
M. Guillen,
Yes Employment, Stock, Stock Option, Patent.
P. Avilés,
Yes Employment, Stock, Stock Option, Patent.
M. L. Ribeiro,
Yes Employment, Stock, Stock Option.
C. Cuevas,
Yes Employment, Stock, Stock Option, Patent.