HER2-targeted PET imaging and therapy of hyaluronan-masked HER2-overexpressing breast cancer Journal Article
| Authors: | Pereira, P. M. R.; Ragupathi, A.; Shmuel, S.; Mandleywala, K.; Viola, N. T.; Lewis, J. S. |
| Article Title: | HER2-targeted PET imaging and therapy of hyaluronan-masked HER2-overexpressing breast cancer |
| Abstract: | 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. © 2019 American Chemical Society. |
| Keywords: | signal transduction; controlled study; protein phosphorylation; drug efficacy; nonhuman; comparative study; positron emission tomography; mouse; gene overexpression; epidermal growth factor receptor 2; animal experiment; animal model; in vitro study; tumor xenograft; molecular imaging; isotope labeling; messenger rna; cancer size; pet imaging; hyaluronic acid; hyaluronidase; trastuzumab; hermes antigen; zirconium 89; autoradiography; internalization; her2; binding assay; cd44; caveolin 1; human epidermal growth factor receptor 2 positive breast cancer; hyaluronan; human; female; priority journal; article; mrna expression level; protein expression level; cav1; hymecromone; jimt-1 cell line; trastuzumab-resistant cell line |
| Journal Title: | Molecular Pharmaceutics |
| Volume: | 17 |
| Issue: | 1 |
| ISSN: | 1543-8384 |
| Publisher: | American Chemical Society |
| Date Published: | 2020-01-06 |
| Start Page: | 327 |
| End Page: | 337 |
| Language: | English |
| DOI: | 10.1021/acs.molpharmaceut.9b01091 |
| PUBMED: | 31804840 |
| PROVIDER: | scopus |
| PMCID: | PMC7218915 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 March 2020 -- Source: Scopus |
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