针对葡萄膜黑色素瘤中MDM2的高通量策略，以逆转放射治疗耐药性
High-throughput strategy for targeting MDM2 in uveal melanoma to reverse radiation therapy resistance.
摘要(中文译文)
葡萄膜黑色素瘤（UM）因其对放射治疗的明显抵抗力而带来了巨大的临床挑战。在这项研究中，采用了一种将机器学习模型与高通量筛选平台相结合的综合策略来鉴定针对MDM2的新型小分子抑制剂，目的是克服这种内在耐药性。转录组测序和机器学习分析确定MDM2是与UM放射治疗耐药性相关的关键基因。单细胞RNA测序数据的整合揭示了导致这种耐药性的关键细胞。体外实验表明，MDM2抑制剂SAR405838通过调节p53激活、抑制细胞迁移和侵袭以及诱导DNA损伤和凋亡，有效提高了耐药UM细胞的放射敏感性。这种新方法为对抗UM对放射治疗的耐药性提供了一种有前景的治疗策略。
Abstract
Uveal melanoma (UM) presents a formidable clinical challenge due to its marked resistance to radiotherapy. In this study, an integrative strategy combining machine learning models with high-throughput screening platforms was employed to identify novel small-molecule inhibitors targeting MDM2, with the aim of overcoming this intrinsic resistance. Transcriptome sequencing and machine learning analysis identified MDM2 as a critical gene associated with UM radiotherapy resistance. Integration of single-cell RNA sequencing data revealed key cells contributing to this resistance. In vitro experiments demonstrated that the MDM2 inhibitor SAR405838 effectively increased radiosensitivity in resistant UM cells by modulating p53 activation, suppressing cell migration and invasion, and inducing DNA damage and apoptosis. This novel approach offers a promising therapeutic strategy for combating UM resistance to radiation therapy.
如何引用
AMA
Qi Zhu, Xi Gong, Sirong Zhang, Jiaqi Zhang, Hongtao Yan. High-throughput strategy for targeting MDM2 in uveal melanoma to reverse radiation therapy resistance.. Cell death discovery. 2026; doi:10.1038/s41420-026-02970-x.
APA
Qi Zhu, Xi Gong, Sirong Zhang, Jiaqi Zhang, Hongtao Yan (2026). High-throughput strategy for targeting MDM2 in uveal melanoma to reverse radiation therapy resistance.. Cell death discovery. https://doi.org/10.1038/s41420-026-02970-x
GB/T 7714
Qi Zhu, Xi Gong, Sirong Zhang, Jiaqi Zhang, Hongtao Yan. High-throughput strategy for targeting MDM2 in uveal melanoma to reverse radiation therapy resistance.[J]. Cell death discovery, 2026 doi:10.1038/s41420-026-02970-x.
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