Sortilin‐related receptor is a druggable therapeutic target in breast cancer
In breast cancer, the currently approved anti‐receptor tyrosine‐protein kinase erbB‐2 (HER2) therapies do not fully meet the expected clinical goals due to therapy resistance. Identifying alternative HER2‐related therapeutic targets could offer a means to overcome these resistance mechanisms. We hav...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-01-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13106 |
| _version_ | 1798035371179638784 |
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| author | Hussein Al‐Akhrass Mika Pietilä Johanna Lilja Ella‐Maria Vesilahti Johanna M. Anttila Heidi M. Haikala Pauliina M. Munne Juha Klefström Emilia Peuhu Johanna Ivaska |
| author_facet | Hussein Al‐Akhrass Mika Pietilä Johanna Lilja Ella‐Maria Vesilahti Johanna M. Anttila Heidi M. Haikala Pauliina M. Munne Juha Klefström Emilia Peuhu Johanna Ivaska |
| author_sort | Hussein Al‐Akhrass |
| collection | DOAJ |
| description | In breast cancer, the currently approved anti‐receptor tyrosine‐protein kinase erbB‐2 (HER2) therapies do not fully meet the expected clinical goals due to therapy resistance. Identifying alternative HER2‐related therapeutic targets could offer a means to overcome these resistance mechanisms. We have previously demonstrated that an endosomal sorting protein, sortilin‐related receptor (SorLA), regulates the traffic and signaling of HER2 and HER3, thus promoting resistance to HER2‐targeted therapy in breast cancer. This study aims to assess the feasibility of targeting SorLA using a monoclonal antibody. Our results demonstrate that anti‐SorLA antibody (SorLA ab) alters the resistance of breast cancer cells to HER2 monoclonal antibody trastuzumab in vitro and in ovo. We found that SorLA ab and trastuzumab combination therapy also inhibits tumor cell proliferation and tumor cell density in a mouse xenograft model of HER2‐positive breast cancer. In addition, SorLA ab inhibits the proliferation of breast cancer patient‐derived explant three‐dimensional cultures. These results provide, for the first time, proof of principle that SorLA is a druggable target in breast cancer. |
| first_indexed | 2024-04-11T20:56:19Z |
| format | Article |
| id | doaj.art-3226b21a139d4cb2aecf7f1e1b37a9ec |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-04-11T20:56:19Z |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-3226b21a139d4cb2aecf7f1e1b37a9ec2022-12-22T04:03:39ZengWileyMolecular Oncology1574-78911878-02612022-01-0116111612910.1002/1878-0261.13106Sortilin‐related receptor is a druggable therapeutic target in breast cancerHussein Al‐Akhrass0Mika Pietilä1Johanna Lilja2Ella‐Maria Vesilahti3Johanna M. Anttila4Heidi M. Haikala5Pauliina M. Munne6Juha Klefström7Emilia Peuhu8Johanna Ivaska9Turku Bioscience Centre University of Turku and Åbo Akademi University FinlandTurku Bioscience Centre University of Turku and Åbo Akademi University FinlandTurku Bioscience Centre University of Turku and Åbo Akademi University FinlandTurku Bioscience Centre University of Turku and Åbo Akademi University FinlandFinnish Cancer Institute FICAN South Helsinki University Hospital & Medical Faculty University of Helsinki FinlandFinnish Cancer Institute FICAN South Helsinki University Hospital & Medical Faculty University of Helsinki FinlandFinnish Cancer Institute FICAN South Helsinki University Hospital & Medical Faculty University of Helsinki FinlandFinnish Cancer Institute FICAN South Helsinki University Hospital & Medical Faculty University of Helsinki FinlandTurku Bioscience Centre University of Turku and Åbo Akademi University FinlandTurku Bioscience Centre University of Turku and Åbo Akademi University FinlandIn breast cancer, the currently approved anti‐receptor tyrosine‐protein kinase erbB‐2 (HER2) therapies do not fully meet the expected clinical goals due to therapy resistance. Identifying alternative HER2‐related therapeutic targets could offer a means to overcome these resistance mechanisms. We have previously demonstrated that an endosomal sorting protein, sortilin‐related receptor (SorLA), regulates the traffic and signaling of HER2 and HER3, thus promoting resistance to HER2‐targeted therapy in breast cancer. This study aims to assess the feasibility of targeting SorLA using a monoclonal antibody. Our results demonstrate that anti‐SorLA antibody (SorLA ab) alters the resistance of breast cancer cells to HER2 monoclonal antibody trastuzumab in vitro and in ovo. We found that SorLA ab and trastuzumab combination therapy also inhibits tumor cell proliferation and tumor cell density in a mouse xenograft model of HER2‐positive breast cancer. In addition, SorLA ab inhibits the proliferation of breast cancer patient‐derived explant three‐dimensional cultures. These results provide, for the first time, proof of principle that SorLA is a druggable target in breast cancer.https://doi.org/10.1002/1878-0261.13106breast cancerHER2HER3receptor traffickingSorLAtrastuzumab |
| spellingShingle | Hussein Al‐Akhrass Mika Pietilä Johanna Lilja Ella‐Maria Vesilahti Johanna M. Anttila Heidi M. Haikala Pauliina M. Munne Juha Klefström Emilia Peuhu Johanna Ivaska Sortilin‐related receptor is a druggable therapeutic target in breast cancer Molecular Oncology breast cancer HER2 HER3 receptor trafficking SorLA trastuzumab |
| title | Sortilin‐related receptor is a druggable therapeutic target in breast cancer |
| title_full | Sortilin‐related receptor is a druggable therapeutic target in breast cancer |
| title_fullStr | Sortilin‐related receptor is a druggable therapeutic target in breast cancer |
| title_full_unstemmed | Sortilin‐related receptor is a druggable therapeutic target in breast cancer |
| title_short | Sortilin‐related receptor is a druggable therapeutic target in breast cancer |
| title_sort | sortilin related receptor is a druggable therapeutic target in breast cancer |
| topic | breast cancer HER2 HER3 receptor trafficking SorLA trastuzumab |
| url | https://doi.org/10.1002/1878-0261.13106 |
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