Human epidermal growth factor receptor 2 (HER2) is a biomarker in breast cancer, and its overexpression is required to initiate therapies using HER2-targeted antibodies. Although trastuzumab is one of the most effective therapeutic antibodies in HER2-overexpressing breast cancer, a significant number of patients do not benefit from this therapy due to inherent or acquired resistance mechanisms. One reported mechanism of resistance is the steric hindering effect caused by the polymeric complex formed between hyaluronan and CD44, thus preventing trastuzumab from binding to HER2. Hyaluronan/CD44 contributes as an obstacle for trastuzumab to bind HER2, but it is also involved in HER2 internalization. In this study, we used zirconium-89 (89Zr)-labeled trastuzumab immunoPET to investigate whether degradation of hyaluronan can resensitize HER2-overexpressing breast cancer cells to trastuzumab. Targeted degradation of endogenously produced hyaluronan and inhibition of its synthesis were achieved by treating trastuzumab-resistant JIMT1 breast cancer cells with hyaluronidase (HLX) and 4-methylumbelliferone (4MU). The 4MU/HLX treatment reduced HER2 internalization by depleting hyaluronan/CD44 and the caveolin-1 (CAV1) endocytic protein, resulting in enhanced membrane-bound 89Zr-labeled trastuzumab. 4MU/HLX enhanced trastuzumab tumor uptake, as evidenced by increased tumor binding of the 89Zr-labeled trastuzumab in JIMT1 tumor xenografts. In vitro mechanistic studies demonstrated a decrease in HER2-mediated oncogenic signaling upon cell treatment with 4MU/HLX. Importantly, 4MU/HLX enhanced trastuzumab efficacy in JIMT1 xenografts. These data showed the utility of 89Zr-labeled trastuzumab as a PET imaging agent to monitor the affinity of the antibody to HER2 during CD44/hyaluronan-specific inhibition with the overall goal of improving trastuzumab therapy.

中文翻译：

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透明质酸掩盖的HER2高表达乳腺癌的HER2靶向PET成像和治疗。

人表皮生长因子受体2（HER2）是乳腺癌中的生物标志物，使用HER2靶向抗体来启动治疗需要其过度表达。尽管曲妥珠单抗是过表达HER2的乳腺癌中最有效的治疗性抗体之一，但由于固有或获得性耐药机制，许多患者无法从该治疗中受益。报道的一种抗性机制是由透明质酸和CD44之间形成的聚合复合物引起的位阻效应，从而阻止了曲妥珠单抗与HER2结合。透明质酸/ CD44是曲妥珠单抗结合HER2的障碍，但它也参与HER2的内在化。在这项研究中，我们使用锆89（89Zr）标记的曲妥珠单抗免疫PET来研究透明质酸的降解是否可以使过度表达HER2的乳腺癌细胞对曲妥珠单抗再敏感。通过用透明质酸酶（HLX）和4-甲基伞形酮（4MU）处理抗曲妥珠单抗的JIMT1乳腺癌细胞，可实现内源性透明质酸的靶向降解及其合成的抑制。4MU / HLX处理通过减少透明质酸/ CD44和小窝蛋白1（CAV1）内吞蛋白减少了HER2内在化，从而增强了与膜结合的89Zr标记的曲妥珠单抗。4MU / HLX增强了曲妥珠单抗的肿瘤摄取，这是由JIMT1肿瘤异种移植物中89Zr标记的曲妥珠单抗的肿瘤结合增加所证明的。体外机理研究表明，用4MU / HLX处理细胞后，HER2介导的致癌信号减少。重要的是，4MU / HLX在JIMT1异种移植物中增强了曲妥珠单抗的功效。这些数据显示了89Zr标记的曲妥珠单抗作为PET显像剂的效用，可在CD44 /透明质酸特异性抑制过程中监测抗体对HER2的亲和力，其总体目标是改善曲妥珠单抗的治疗。