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FoxM1 介导曲妥珠单抗和紫杉醇耐药。

FoxM1 mediates resistance to herceptin and paclitaxel.

机构信息

Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, Chicago, Illinois 60607-7170, USA.

出版信息

Cancer Res. 2010 Jun 15;70(12):5054-63. doi: 10.1158/0008-5472.CAN-10-0545. Epub 2010 Jun 8.

DOI:10.1158/0008-5472.CAN-10-0545
PMID:20530690
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2893542/
Abstract

Inherent and acquired therapeutic resistance in breast cancer remains a major clinical challenge. In human breast cancer samples, overexpression of the oncogenic transcription factor FoxM1 has been suggested to be a marker of poor prognosis. In this study, we report that FoxM1 overexpression confers resistance to the human epidermal growth factor receptor 2 monoclonal antibody Herceptin and microtubule-stabilizing drug paclitaxel, both as single agents and in combination. FoxM1 altered microtubule dynamics to protect tumor cells from paclitaxel-induced apoptosis. Mechanistic investigations revealed that the tubulin-destabilizing protein Stathmin, whose expression also confers resistance to paclitaxel, is a direct transcriptional target of FoxM1. Significantly, attenuating FoxM1 expression by small interfering RNA or an alternate reading frame (ARF)-derived peptide inhibitor increased therapeutic sensitivity. Our findings indicate that targeting FoxM1 could relieve therapeutic resistance in breast cancer.

摘要

在乳腺癌中，内在和获得性治疗抵抗仍然是一个主要的临床挑战。在人类乳腺癌样本中，致癌转录因子 FoxM1 的过表达被认为是预后不良的标志物。在这项研究中，我们报告 FoxM1 的过表达赋予了人表皮生长因子受体 2 单克隆抗体赫赛汀和微管稳定剂紫杉醇的耐药性，无论是单独使用还是联合使用。FoxM1 改变微管动力学，以保护肿瘤细胞免受紫杉醇诱导的凋亡。机制研究表明，微管不稳定蛋白 Stathmin 的表达也赋予了紫杉醇的耐药性，是 FoxM1 的直接转录靶标。重要的是，通过小干扰 RNA 或替代阅读框 (ARF) 衍生肽抑制剂降低 FoxM1 的表达增加了治疗敏感性。我们的研究结果表明，靶向 FoxM1 可能会缓解乳腺癌的治疗抵抗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e4d/2893542/73ade8569fd2/nihms201263f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e4d/2893542/811ca97ddc06/nihms201263f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e4d/2893542/027243160fbc/nihms201263f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e4d/2893542/07bb0547bc3f/nihms201263f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e4d/2893542/00aee40bc137/nihms201263f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e4d/2893542/9fbac9c79930/nihms201263f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e4d/2893542/73ade8569fd2/nihms201263f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e4d/2893542/811ca97ddc06/nihms201263f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e4d/2893542/027243160fbc/nihms201263f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e4d/2893542/07bb0547bc3f/nihms201263f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e4d/2893542/00aee40bc137/nihms201263f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e4d/2893542/9fbac9c79930/nihms201263f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e4d/2893542/73ade8569fd2/nihms201263f6.jpg

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Clin Cancer Res. 2009 Dec 15;15(24):7479-7491. doi: 10.1158/1078-0432.CCR-09-0636.
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A conserved phosphorylation site within the forkhead domain of FoxM1B is required for its activation by cyclin-CDK1.FoxM1B叉头结构域内一个保守的磷酸化位点是其被细胞周期蛋白-CDK1激活所必需的。
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Mol Biol Rep. 2024 Aug 21;51(1):927. doi: 10.1007/s11033-024-09863-1.
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Acta Biochim Biophys Sin (Shanghai). 2024 Jul 31;56(9):1289-1299. doi: 10.3724/abbs.2024084.
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YAP inhibition overcomes adaptive resistance in HER2-positive gastric cancer treated with trastuzumab via the AKT/mTOR and ERK/mTOR axis.YAP 抑制通过 AKT/mTOR 和 ERK/mTOR 轴克服曲妥珠单抗治疗的 HER2 阳性胃癌的获得性耐药。
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Gefitinib (Iressa) represses FOXM1 expression via FOXO3a in breast cancer.吉非替尼（易瑞沙）通过FOXO3a抑制乳腺癌中FOXM1的表达。
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