MT-125抑制非肌球蛋白IIA和IIB，延长胶质母细胞瘤的生存期

IF 42.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2025-06-10 DOI:10.1016/j.cell.2025.05.019

Rajappa S. Kenchappa, Laszlo Radnai, Erica J. Young, Natanael Zarco, Li Lin, Athanassios Dovas, Christian T. Meyer, Ashley Haddock, Alice Hall, Katalin Toth, Peter Canoll, Naveen K.H. Nagaiah, Gavin Rumbaugh, Michael D. Cameron, Theodore M. Kamenecka, Patrick R. Griffin, Courtney A. Miller, Steven S. Rosenfeld

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引用次数: 0

摘要

胶质母细胞瘤（GBM）是最致命的原发性脑肿瘤。在这里，我们报告了我们对MT-125的研究，一种非肌肉肌球蛋白II的小分子抑制剂。MT-125具有高脑外显率和良好的安全性，可阻断GBM侵袭和细胞分裂，并延长小鼠GBM模型的生存期。通过损害线粒体裂变，MT-125增加氧化还原应激和随之而来的DNA损伤，并与放疗协同作用。MT-125还通过氧化还原应激驱动的机制诱导癌基因对PDGFR信号通路的依赖，并在体外与fda批准的PDGFR和mTOR抑制剂协同作用。与此一致，我们发现MT-125联合舒尼替尼（PDGFR抑制剂）或paxalisib（联合磷脂酰肌醇3-激酶(PI3K)/mTOR抑制剂）比单独使用任何一种药物都能显著提高原位GBM模型的生存率。我们的研究结果表明，MT-125是一种一流的治疗方法，在治疗GBM方面具有很强的临床潜力。

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MT-125 inhibits non-muscle myosin IIA and IIB and prolongs survival in glioblastoma

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MT-125 inhibits non-muscle myosin IIA and IIB and prolongs survival in glioblastoma

Glioblastoma (GBM) is the most lethal of primary brain tumors. Here, we report our studies of MT-125, a small-molecule inhibitor of non-muscle myosin II. MT-125 has high brain penetrance and an excellent safety profile, blocks GBM invasion and cytokinesis, and prolongs survival in murine GBM models. By impairing mitochondrial fission, MT-125 increases redox stress and consequent DNA damage, and it synergizes with radiotherapy. MT-125 also induces oncogene addiction to PDGFR signaling through a mechanism that is driven by redox stress, and it synergizes with FDA-approved PDGFR and mTOR inhibitors in vitro. Consistent with this, we find that combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor, significantly improves survival in orthotopic GBM models over either drug alone. Our results demonstrate that MT-125 is a first-in-class therapeutic that has strong clinical potential for the treatment of GBM.

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.