以不可药用磷酸酶为靶点,通过抑制多种致癌激酶克服曲妥珠单抗抗药性

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Resistance Updates Pub Date : 2024-07-14 DOI:10.1016/j.drup.2024.101118
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引用次数: 0

摘要

目的靶向治疗的抗药性是癌症治疗的关键障碍之一。在治疗 HER2+ 癌症的过程中,曲妥珠单抗经常会产生抗药性。蛋白酪氨酸磷酸酶(PTPs)在曲妥珠单抗耐药中的作用尚不十分清楚。在这项研究中,我们旨在找出影响曲妥珠单抗耐药性的关键 PTPs,并设计出一种新的应对策略。方法利用四个公开数据集筛选与 HER2+ 乳腺癌中曲妥珠单抗反应性相关的 PTP 候选者。酪氨酸激酶(TK)阵列用于鉴定与蛋白酪氨酸磷酸受体O型(PTPRO)增强曲妥珠单抗敏感性相关的激酶。在细胞模型、转基因小鼠模型和人类癌细胞系衍生的异种移植模型中,测试了曲妥珠单抗共轭硅纳米粒子中的小激活 RNA(saRNA)对 PTPRO 的上调和抗药性缓解的功效。PTPRO 可使多个 TK(包括以前被忽视的底物 ERBB3)去磷酸化,从而抑制与耐药性相关的多种致癌通路。值得注意的是,以前被认为 "不可药用 "的 PTPRO 被载入 saRNA 的纳米颗粒有效上调。上调的 PTPRO 同时抑制了 ERBB3、ERBB2 和下游 SRC 信号通路,从而抵消了曲妥珠单抗的耐药性。
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Targeting undruggable phosphatase overcomes trastuzumab resistance by inhibiting multi-oncogenic kinases

Aims

Resistance to targeted therapy is one of the critical obstacles in cancer management. Resistance to trastuzumab frequently develops in the treatment for HER2+ cancers. The role of protein tyrosine phosphatases (PTPs) in trastuzumab resistance is not well understood. In this study, we aim to identify pivotal PTPs affecting trastuzumab resistance and devise a novel counteracting strategy.

Methods

Four public datasets were used to screen PTP candidates in relation to trastuzumab responsiveness in HER2+ breast cancer. Tyrosine kinase (TK) arrays were used to identify kinases that linked to protein tyrosine phosphate receptor type O (PTPRO)-enhanced trastuzumab sensitivity. The efficacy of small activating RNA (saRNA) in trastuzumab-conjugated silica nanoparticles was tested for PTPRO upregulation and resistance mitigation in cell models, a transgenic mouse model, and human cancer cell line-derived xenograft models.

Results

PTPRO was identified as the key PTP which influences trastuzumab responsiveness and patient survival. PTPRO de-phosphorated several TKs, including the previously overlooked substrate ERBB3, thereby inhibiting multiple oncogenic pathways associated with drug resistance. Notably, PTPRO, previously deemed “undruggable,” was effectively upregulated by saRNA-loaded nanoparticles. The upregulated PTPRO simultaneously inhibited ERBB3, ERBB2, and downstream SRC signaling pathways, thereby counteracting trastuzumab resistance.

Conclusions

Antibody-conjugated saRNA represents an innovative approach for targeting “undruggable” PTPs.

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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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