HER2-Targeted PET Imaging and Therapy of Hyaluronan-Masked HER2-Overexpressing Breast Cancer
HER2-Targeted PET Imaging and Therapy of Hyaluronan-Masked HER2-Overexpressing Breast Cancer
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DOI：
10.1021/acs.molpharmaceut.9b01091
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发表时间：
2020-01-01
影响因子：
4.9
通讯作者：
Lewis, Jason S.
中科院分区：
文献类型：
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作者：
Pereira, Patricia M. R.;Ragupathi, Ashwin;Lewis, Jason S.
人表皮生长因子受体2(HER2)是乳腺癌的一个生物标志物，它的过度表达是使用HER2靶向抗体进行治疗所必需的。尽管曲妥珠单抗是治疗HER2过表达乳腺癌最有效的治疗抗体之一，但由于固有或获得性耐药机制，相当数量的患者无法从这种治疗中受益。一种已报道的耐药机制是透明质酸与CD44之间形成的聚合物复合体引起的空间位阻效应，从而阻止曲妥珠单抗与HER2结合。透明质酸/CD44是曲妥珠单抗与HER2结合的障碍，但也参与了HER2的内化。在这项研究中，我们使用锆-(Zr-)标记的曲妥珠单抗免疫PET来研究透明质酸降解是否能使HER2高表达的乳腺癌细胞对曲妥珠单抗重新增敏。用透明质酸酶(HLX)和4-甲基伞形酮(4MU)处理耐曲妥珠单抗的JIMT1乳腺癌细胞，可以靶向降解内源性产生的透明质酸并抑制其合成。4MU/HLX处理通过耗尽透明质酸/CD44和小窝蛋白-1(CAV1)内吞蛋白而减少HER2的内化，导致膜结合的Zr-89标记的曲妥珠单抗增强。4MU/HLX可增强曲妥珠单抗对肿瘤的摄取，表现为ZR-89标记的曲妥珠单抗在JIMT1肿瘤移植瘤中的结合增强。体外机制研究表明，4MU/HLX处理细胞后，HER2介导的致癌信号减少。重要的是，4MU/HLX增强了曲妥珠单抗在JIMT1异种移植中的疗效。这些数据表明，在CD44/透明质酸特异性抑制过程中，以改善曲妥珠单抗治疗的总体目标为目标，用Zr-标记的曲妥珠单抗作为PET显像剂来监测抗体对HER2的亲和力。
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 (Zr-89)-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 Zr-89-labeled trastuzumab. 4MU/HLX enhanced trastuzumab tumor uptake, as evidenced by increased tumor binding of the Zr-89-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 Zr-89-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.