High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer.
Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is an aggressive subtype of this disease. Targeted treatment has improved outcome, but there is still a need for new therapeutic strategies as some patients respond poorly to treatment. Our aim was to identify compounds that sub...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0280507 |
| _version_ | 1797937987891232768 |
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| author | Lisa Svartdal Normann Mads Haugland Haugen Vesa Hongisto Miriam Ragle Aure Suvi-Katri Leivonen Vessela N Kristensen Andliena Tahiri Olav Engebraaten Kristine Kleivi Sahlberg Gunhild Mari Mælandsmo |
| author_facet | Lisa Svartdal Normann Mads Haugland Haugen Vesa Hongisto Miriam Ragle Aure Suvi-Katri Leivonen Vessela N Kristensen Andliena Tahiri Olav Engebraaten Kristine Kleivi Sahlberg Gunhild Mari Mælandsmo |
| author_sort | Lisa Svartdal Normann |
| collection | DOAJ |
| description | Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is an aggressive subtype of this disease. Targeted treatment has improved outcome, but there is still a need for new therapeutic strategies as some patients respond poorly to treatment. Our aim was to identify compounds that substantially affect viability in HER2+ breast cancer cells in response to combinatorial treatment. We performed a high-throughput drug screen of 278 compounds in combination with trastuzumab and lapatinib using two HER2+ breast cancer cell lines (KPL4 and SUM190PT). The most promising drugs were validated in vitro and in vivo, and downstream molecular changes of the treatments were analyzed. The screen revealed multiple drugs that could be used in combination with lapatinib and/or trastuzumab. The Src-inhibitor dasatinib showed the largest combinatorial effect together with lapatinib in the KPL4 cell line compared to treatment with dasatinib alone (p < 0.01). In vivo, only lapatinib significantly reduced tumor growth (p < 0.05), whereas dasatinib alone, or in combination with lapatinib, did not show significant effects. Protein analyses of the treated xenografts showed significant alterations in protein levels compared to untreated controls, suggesting that all drugs reached the tumor and exerted a measurable effect. In silico analyses suggested activation of apoptosis and reduced activity of survival pathways by all treatments, but the opposite pattern was observed for the combinatorial treatment compared to lapatinib alone. |
| first_indexed | 2024-04-10T18:52:45Z |
| format | Article |
| id | doaj.art-a267b2c834e74bde9dda62efe4aa7af4 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-10T18:52:45Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-a267b2c834e74bde9dda62efe4aa7af42023-02-01T05:31:31ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01181e028050710.1371/journal.pone.0280507High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer.Lisa Svartdal NormannMads Haugland HaugenVesa HongistoMiriam Ragle AureSuvi-Katri LeivonenVessela N KristensenAndliena TahiriOlav EngebraatenKristine Kleivi SahlbergGunhild Mari MælandsmoHuman epidermal growth factor receptor 2-positive (HER2+) breast cancer is an aggressive subtype of this disease. Targeted treatment has improved outcome, but there is still a need for new therapeutic strategies as some patients respond poorly to treatment. Our aim was to identify compounds that substantially affect viability in HER2+ breast cancer cells in response to combinatorial treatment. We performed a high-throughput drug screen of 278 compounds in combination with trastuzumab and lapatinib using two HER2+ breast cancer cell lines (KPL4 and SUM190PT). The most promising drugs were validated in vitro and in vivo, and downstream molecular changes of the treatments were analyzed. The screen revealed multiple drugs that could be used in combination with lapatinib and/or trastuzumab. The Src-inhibitor dasatinib showed the largest combinatorial effect together with lapatinib in the KPL4 cell line compared to treatment with dasatinib alone (p < 0.01). In vivo, only lapatinib significantly reduced tumor growth (p < 0.05), whereas dasatinib alone, or in combination with lapatinib, did not show significant effects. Protein analyses of the treated xenografts showed significant alterations in protein levels compared to untreated controls, suggesting that all drugs reached the tumor and exerted a measurable effect. In silico analyses suggested activation of apoptosis and reduced activity of survival pathways by all treatments, but the opposite pattern was observed for the combinatorial treatment compared to lapatinib alone.https://doi.org/10.1371/journal.pone.0280507 |
| spellingShingle | Lisa Svartdal Normann Mads Haugland Haugen Vesa Hongisto Miriam Ragle Aure Suvi-Katri Leivonen Vessela N Kristensen Andliena Tahiri Olav Engebraaten Kristine Kleivi Sahlberg Gunhild Mari Mælandsmo High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer. PLoS ONE |
| title | High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer. |
| title_full | High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer. |
| title_fullStr | High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer. |
| title_full_unstemmed | High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer. |
| title_short | High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer. |
| title_sort | high throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with her2 targeting drugs in breast cancer |
| url | https://doi.org/10.1371/journal.pone.0280507 |
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