PO.ET09.05 · 实验与分子治疗
PM54抑制WNT/beta-catenin信号传导并在胃癌模型中与化疗产生协同作用
PM54 suppresses WNT/beta-catenin signaling and synergizes with chemotherapy in gastric cancer models
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：PM54是一种lurbinectedin类似物，可结合富含CG的启动子区域，诱导转录阻断、DNA双链断裂和S期阻滞，最终导致细胞凋亡。在胃癌模型中，它驱动早期转录重编程，抑制细胞周期和DNA修复通路，并在体内表现出强效的单药抗肿瘤疗效。我们旨在评估PM54在胃癌中的抗肿瘤疗效，并评估其与标准化疗药物的潜在协同作用。
方法：使用TCF/LEF报告基因检测和通路生物标志物分析评估胃癌细胞系中的WNT/beta-catenin活性。通过联合指数分析量化其与5-氟尿嘧啶（5-FU）和顺铂的药物相互作用。在接受PM54、化疗或联合治疗的胃癌异种移植瘤中测试体内疗效，并随时间监测肿瘤生长。
结果：作为单药，PM54显著抑制WNT/beta-catenin通路，在治疗后6小时使TCF/beta-catenin驱动的转录降低约40%，18小时降低超过70%。在体外，PM54在弥漫型胃癌细胞系（HGC-27和Hs746T）中与5-氟尿嘧啶（5-FU）表现出强协同作用，在HGC-27细胞中与顺铂表现出强协同作用。在体内，用PM54（0.9 mg/kg；第0天和第7天）治疗荷HGC-27异种移植瘤的小鼠产生了强抗肿瘤活性。在第10天（安慰剂组的最后存活日），安慰剂组小鼠的中位肿瘤体积为1612 mm³，而5-FU治疗组为1375 mm³、顺铂治疗组为1423 mm³、PM54治疗组为616 mm³（p = 0.019）。PM54与5-FU或顺铂的联合治疗明显优于相应的单药治疗，中位ΔT/ΔC（%）分别为29.4（PM54）、84.2（5-FU）和15.0（联合）；顺铂也观察到类似模式，ΔT/ΔC（%）为29.4（PM54）、85.7（顺铂）和21.5（联合）。
结论：PM54抑制WNT/beta-catenin信号传导并增强化疗在胃癌模型中的疗效。这些发现支持将其开发为合理的联合治疗方案，以改善患者预后。
查看英文原文 English abstract
Background: PM54 is a lurbinectedin analog that binds CG-rich promoter regions, inducing transcriptional blockade, DNA double-strand breaks, and S-phase arrest culminating in apoptosis. In gastric cancer models, it drives early transcriptional reprogramming with repression of cell-cycle and DNA repair pathways and demonstrates potent single-agent antitumor efficacy in vivo. We aimed to evaluate the antitumor efficacy of PM54 in gastric cancer and to assess its potential synergy with standard chemotherapeutic agents
Methods: WNT/beta-catenin activity was assessed in gastric cancer cell lines using TCF/LEF reporter assays and pathway biomarker analysis. Drug interactions with 5-fluorouracil (5-FU) and cisplatin were quantified by combination index analysis. In vivo efficacy was tested in gastric cancer xenografts treated with PM54, chemotherapy, or combinations, with tumor growth monitored over time.
Results: As a single agent, PM54 markedly inhibited the WNT/beta-catenin pathway, reducing TCF/beta-catenin-driven transcription by about 40% at 6 hours and over 70% at 18 hours post-treatment. In vitro, PM54 showed strong synergy with 5-fluorouracil (5-FU) in diffuse-type gastric cancer cell lines (HGC-27 and Hs746T) and with cisplatin in HGC-27 cells. In vivo, treatment with PM54 (0.9 mg/kg; days 0 and 7) of mice bearing HGC-27 xenograft tumors resulted in strong antitumor activity. On day 10 (last day of survival in the placebo-treated group), the median tumor volume in placebo-treated mice was 1612 mm³, compared with mice treated with 5-FU (1375 mm³), cisplatin (1423 mm³), and PM54 (616 mm³; p = 0.019). The combination of PM54 with 5-FU or cisplatin resulted in clearly superior performance to the corresponding therapies, with a median ΔT/ΔC (%) of 29.4 (PM54), 84.2 (5-FU), and 15.0 (combination); a similar pattern was observed with cisplatin, with ΔT/ΔC (%) 29.4 (PM54), 85.7 (cisplatin), and 21.5 (combination).
Conclusions: PM54 represses WNT/beta-catenin signaling and enhances the efficacy of chemotherapy in gastric cancer models. These findings support its development in rational combination regimens to improve patient outcomes.
利益披露 Disclosure
F. Gutierrez Alvarez,
Yes Employment, Stock, Stock Option.
G. Santamaria,
Yes Employment, Stock, Stock Option.
M. Martínez Diez,
Yes Employment, Stock, 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.