靶向不可成药的磷酸酶通过抑制多种致癌激酶克服曲妥珠单抗耐药性。
Targeting undruggable phosphatase overcomes trastuzumab resistance by inhibiting multi-oncogenic kinases.
机构信息
Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, and Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, China; Zhuhai Institute of Jinan University, Zhuhai, China.
State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, and Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, China; Zhuhai Institute of Jinan University, Zhuhai, China; Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China; Department of Hematology, University of Groningen, University Medical Center Groningen, the Netherlands; Shantou University Medical College, Shantou, China.
出版信息
Drug Resist Updat. 2024 Sep;76:101118. doi: 10.1016/j.drup.2024.101118. Epub 2024 Jul 14.
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.
目的
靶向治疗耐药是癌症治疗中的关键障碍之一。曲妥珠单抗治疗 HER2 癌症时经常会产生耐药性。蛋白酪氨酸磷酸酶（PTPs）在曲妥珠单抗耐药中的作用尚未得到充分了解。本研究旨在确定影响曲妥珠单抗耐药的关键 PTP，并设计一种新的对抗策略。
方法
使用四个公共数据集筛选与曲妥珠单抗治疗 HER2 乳腺癌的反应性相关的 PTP 候选物。酪氨酸激酶（TK）阵列用于鉴定与蛋白酪氨酸磷酸酯酶受体 O（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源癌细胞系衍生的异种移植模型中，测试了用于 PTPRO 上调和耐药缓解的小激活 RNA（saRNA）在曲妥珠单抗缀合的硅纳米颗粒中的功效。
结果
PTPRO 被确定为影响曲妥珠单抗反应性和患者生存的关键 PTP。PTPRO 去磷酸化了几种 TK，包括先前被忽视的底物 ERBB3，从而抑制了与耐药相关的多种致癌途径。值得注意的是，先前被认为“不可成药”的 PTPRO 可被负载 saRNA 的纳米颗粒有效上调。上调的 PTPRO 同时抑制 ERBB3、ERBB2 和下游 SRC 信号通路，从而对抗曲妥珠单抗耐药性。
结论
抗体偶联的 saRNA 代表了针对“不可成药”PTP 的创新方法。
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