crVDAC3 alleviates ferroptosis by impeding HSPB1 ubiquitination and confers trastuzumab deruxtecan resistance in HER2-low breast cancer

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Resistance Updates Pub Date : 2024-08-06 DOI:10.1016/j.drup.2024.101126
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Abstract

Aims

With the wide application of trastuzumab deruxtecan (T-DXd), the survival of HER2-low breast cancer patients is dramatically improved. However, resistance to T-DXd still exists in a subset of patients, and the molecular mechanism remains unclear.

Methods

An in vivo shRNA lentiviral library functional screening was performed to identify potential circular RNA (crRNA) that mediates T-DXd resistance. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and co-immunoprecipitation assays were conducted to investigate the molecular mechanism. Ferroptosis was detected using C11-BODIPY, Liperfluo, FerroOrange staining, glutathione quantification, malondialdehyde quantification, and transmission electron microscopy. Molecular docking, virtual screening, and patient-derived xenograft (PDX) models were used to validate therapeutic agents.

Results

VDAC3-derived crRNA (crVDAC3) ranked first in functional shRNA library screening. Knockdown of crVDAC3 increased the sensitivity of HER2-low breast cancer cells to T-DXd treatment. Further mechanistic research revealed that crVDAC3 specifically binds to HSPB1 protein and inhibits its ubiquitination degradation, leading to intracellular accumulation and increased levels of HSPB1 protein. Notably, suppression of crVDAC3 dramatically increases excessive ROS levels and labile iron pool accumulation. Inhibition of crVDAC3 induces ferroptosis in breast cancer cells by reducing HSPB1 expression, thereby mediating T-DXd resistance. Through virtual screening and experimental validation, we identified that paritaprevir could effectively bind to crVDAC3 and prevent its interaction with HSPB1 protein, thereby increasing ubiquitination degradation of HSPB1 protein to overcome T-DXd resistance. Finally, we validated the enhanced therapeutic efficacy of T-DXd by paritaprevir in a HER2-low PDX model.

Conclusion

This finding reveals the molecular mechanisms underlying T-DXd resistance in HER2-low breast cancer. Our study provides a new strategy to overcome T-DXd resistance by inhibiting the interaction between crVDAC3 and HSPB1 protein.

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crVDAC3通过阻碍HSPB1泛素化减轻铁变态反应,并使HER2低下的乳腺癌产生曲妥珠单抗德鲁司坦抗性。
目的:随着曲妥珠单抗德鲁司康(T-DXd)的广泛应用,HER2低下乳腺癌患者的生存率得到了显著提高。然而,仍有一部分患者对 T-DXd 存在耐药性,其分子机制仍不清楚:方法:进行了体内 shRNA 慢病毒库功能筛选,以确定介导 T-DXd 耐药性的潜在环状 RNA(crRNA)。为研究其分子机制,进行了 RNA 拉取、质谱分析、RNA 免疫沉淀和共免疫沉淀试验。利用 C11-BODIPY、Liperfluo、FerroOrange 染色、谷胱甘肽定量、丙二醛定量和透射电子显微镜检测铁中毒。分子对接、虚拟筛选和患者异种移植(PDX)模型被用来验证治疗药物:结果:VDAC3衍生的crRNA(crVDAC3)在功能性shRNA文库筛选中排名第一。敲除crVDAC3可提高HER2低的乳腺癌细胞对T-DXd治疗的敏感性。进一步的机理研究发现,crVDAC3 能特异性地与 HSPB1 蛋白结合并抑制其泛素化降解,从而导致 HSPB1 蛋白在细胞内的积累和水平升高。值得注意的是,抑制crVDAC3会显著增加过量的ROS水平和易损铁池的积累。抑制crVDAC3可通过降低HSPB1的表达诱导乳腺癌细胞的铁变态反应,从而介导T-DXd耐药性。通过虚拟筛选和实验验证,我们发现帕立替韦能有效结合crVDAC3,阻止其与HSPB1蛋白的相互作用,从而增加HSPB1蛋白的泛素化降解,克服T-DXd耐药性。最后,我们在HER2-low PDX模型中验证了帕立特韦增强T-DXd疗效的作用:结论:这一发现揭示了HER2-low乳腺癌T-DXd耐药的分子机制。我们的研究通过抑制crVDAC3和HSPB1蛋白之间的相互作用,为克服T-DXd耐药性提供了一种新策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Drug Resistance Updates
Drug Resistance Updates 医学-药学
CiteScore
26.20
自引率
11.90%
发文量
32
审稿时长
29 days
期刊介绍: Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research
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