Abstract：
OBJECTIVE: 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.
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.
摘要：
目的：对靶向治疗的耐药是癌症治疗的关键障碍之一。在HER2+癌症的治疗中经常发展对曲妥珠单抗的抗性。蛋白酪氨酸磷酸酶（PTP）在曲妥珠单抗耐药性中的作用尚不清楚。在这项研究中,我们的目标是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来筛选与HER2+乳腺癌患者曲妥珠单抗反应性相关的候选PTP。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）增强的曲妥珠单抗敏感性相关的激酶。在细胞模型中，测试了曲妥珠单抗缀合的二氧化硅纳米颗粒中的小激活RNA（saRNA）的PTPRO上调和抗性缓解的功效，转基因小鼠模型，和人类癌细胞系来源的异种移植模型。
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去磷酸化了几个TK，包括以前被忽视的底物ERBB3，从而抑制与耐药性相关的多个致癌途径。值得注意的是,PTPRO,以前被认为是不可吸毒的，“被负载saRNA的纳米颗粒有效地上调。上调的PTPRO同时抑制ERBB3、ERBB2和下游SRC信号通路,从而抵消曲妥珠单抗耐药。
结论：抗体缀合的saRNA代表了靶向“不可药物”PTP的创新方法。
方法：使用四个公共数据集来筛选与HER2+乳腺癌患者曲妥珠单抗反应性相关的候选PTP。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）增强的曲妥珠单抗敏感性相关的激酶。在细胞模型中，测试了曲妥珠单抗缀合的二氧化硅纳米颗粒中的小激活RNA（saRNA）的PTPRO上调和抗性缓解的功效，转基因小鼠模型，和人类癌细胞系来源的异种移植模型。
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去磷酸化了几个TK，包括以前被忽视的底物ERBB3，从而抑制与耐药性相关的多个致癌途径。值得注意的是,PTPRO,以前被认为是不可吸毒的，“被负载saRNA的纳米颗粒有效地上调。上调的PTPRO同时抑制ERBB3、ERBB2和下游SRC信号通路,从而抵消曲妥珠单抗耐药。
结论：抗体缀合的saRNA代表了靶向“不可药物”PTP的创新方法。
