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

中文翻译：

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靶向不可成药磷酸酶通过抑制多致癌激酶克服曲妥珠单抗耐药性


对靶向治疗的耐药性是癌症治疗的关键障碍之一。在 HER2 癌症的治疗中经常出现曲妥珠单抗耐药性。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性的关键 PTP，并设计一种新的对抗策略。使用四个公共数据集来筛选与 HER2 乳腺癌曲妥珠单抗反应相关的 PTP 候选药物。酪氨酸激酶 (TK) 阵列用于鉴定与 O 型蛋白酪氨酸磷酸受体 (PTPRO) 增强的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来源的异种移植模型中，测试了曲妥珠单抗缀合的二氧化硅纳米颗粒中小激活 RNA (saRNA) 的 PTPRO 上调和耐药性减轻的功效。 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 使多种 TK 去磷酸化，包括以前被忽视的底物 ERBB3，从而抑制与耐药性相关的多种致癌途径。值得注意的是，以前被认为“不可成药”的 PTPRO 被负载 saRNA 的纳米粒子有效上调。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性。抗体偶联的 saRNA 代表了一种针对“不可成药”PTP 的创新方法。