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在rhabdomyosarcoma中对蛋白质平衡网络的活体操纵

Kristen Kwong¹, Yue Pan¹, Jacqueline Morales¹

¹Department of Pediatrics, Division of Oncology, University of California San Francisco, San Francisco, CA 94143, USA.

|August 29, 2025

概括

用p97抑制剂向蛋白质稳态 (蛋白质稳态) 是对肌肉瘤 (RMS) 治疗有前途的. 这种方法激活了未折叠的蛋白质反应 (UPR) 并诱导癌细胞死亡,提供了一个新的治疗策略.

科学领域:

分子生物学
癌症生物学
药物发现

背景情况:

蛋白质平衡 (蛋白质平衡) 网络对于细胞健康至关重要,并且在癌症中经常受到调节.
儿科软组织肉瘤 (RMS) 对复发患者的治疗选择有限.
使用MAL3-101抑制热冲击蛋白70-kD (HSP70) 伴侣,通过未折叠蛋白反应 (UPR) 激活诱导RMS细胞死亡.

研究的目的:

研究蛋白质稳定抑制剂作为RMS的治疗策略.
为了选可能模仿MAL3-101体内效应的蛋白质稳定成分.
在RMS中探索向VCP (p97 ATPase) 的治疗潜力.

主要方法:

查蛋白质稳定组件
在RMS细胞中抑制VCP (p97 ATPase) 和评估UPR激活和亡.
在小鼠模型和患者衍生异体移植中评估临床前的p97抑制剂.
对抗性瘤进行RNA测序以识别生物标志物.

主要成果:

与MAL3-101类似的VCP抑制激活了UPR并诱导了RMS亡.
与MAL3-101相比,临床前的p97抑制剂表现出改善的生物可用性和抗瘤活性.
瘤异位移植对p97抑制剂的敏感性有所变化,耐药性与自性增加有关.

结论:

蛋白质稳定抑制,特别是针对VCP,是减缓RMS生长的可行治疗策略.
抗性瘤中自的增加表明它是蛋白质稳定性适应性的生物标志物.
针对蛋白质稳定网络中的补偿机制可能导致RMS的协同治疗结果.

关键词:

没有.临床前治疗方法蛋白质平衡骨髓瘤癌症不折叠的蛋白质反应

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