Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells
In pre-clinical studies, triple-negative breast cancer (TNBC) cells have demonstrated sensitivity to the multi-targeted kinase inhibitor dasatinib; however, clinical trials with single-agent dasatinib showed limited efficacy in unselected populations of breast cancer, including TNBC. To study potent...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/4/548 |
| _version_ | 1797763449201098752 |
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| author | Patricia Gaule Nupur Mukherjee Brendan Corkery Alex J. Eustace Kathy Gately Sandra Roche Robert O’Connor Kenneth J. O’Byrne Naomi Walsh Michael J. Duffy John Crown Norma O’Donovan |
| author_facet | Patricia Gaule Nupur Mukherjee Brendan Corkery Alex J. Eustace Kathy Gately Sandra Roche Robert O’Connor Kenneth J. O’Byrne Naomi Walsh Michael J. Duffy John Crown Norma O’Donovan |
| author_sort | Patricia Gaule |
| collection | DOAJ |
| description | In pre-clinical studies, triple-negative breast cancer (TNBC) cells have demonstrated sensitivity to the multi-targeted kinase inhibitor dasatinib; however, clinical trials with single-agent dasatinib showed limited efficacy in unselected populations of breast cancer, including TNBC. To study potential mechanisms of resistance to dasatinib in TNBC, we established a cell line model of acquired dasatinib resistance (231-DasB). Following an approximately three-month exposure to incrementally increasing concentrations of dasatinib (200 nM to 500 nM) dasatinib, 231-DasB cells were resistant to the agent with a dasatinib IC<sub>50</sub> value greater than 5 μM compared to 0.04 ± 0.001 µM in the parental MDA-MB-231 cells. 231-DasB cells also showed resistance (2.2-fold) to the Src kinase inhibitor PD180970. Treatment of 231-DasB cells with dasatinib did not inhibit phosphorylation of Src kinase. The 231-DasB cells also had significantly increased levels of p-Met compared to the parental MDA-MB-231 cells, as measured by luminex, and resistant cells demonstrated a significant increase in sensitivity to the c-Met inhibitor, CpdA, with an IC<sub>50</sub> value of 1.4 ± 0.5 µM compared to an IC<sub>50</sub> of 6.8 ± 0.2 µM in the parental MDA-MB-231 cells. Treatment with CpdA decreased p-Met and p-Src in both 231-DasB and MDA-MB-231 cells. Combined treatment with dasatinib and CpdA significantly inhibited the growth of MDA-MB-231 parental cells and prevented the emergence of dasatinib resistance. If these in vitro findings can be extrapolated to human cancer treatment, combined treatment with dasatinib and a c-Met inhibitor may block the development of acquired resistance and improve response rates to dasatinib treatment in TNBC. |
| first_indexed | 2024-03-12T19:42:46Z |
| format | Article |
| id | doaj.art-e16a74b79fd843269694366529e91d6b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T19:42:46Z |
| publishDate | 2019-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-e16a74b79fd843269694366529e91d6b2023-08-02T03:47:15ZengMDPI AGCancers2072-66942019-04-0111454810.3390/cancers11040548cancers11040548Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer CellsPatricia Gaule0Nupur Mukherjee1Brendan Corkery2Alex J. Eustace3Kathy Gately4Sandra Roche5Robert O’Connor6Kenneth J. O’Byrne7Naomi Walsh8Michael J. Duffy9John Crown10Norma O’Donovan11Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin D09 NR58, IrelandMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin D09 NR58, IrelandMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin D09 NR58, IrelandMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin D09 NR58, IrelandTrinity Translational Medicine Institute, St. James’s Hospital Dublin, Dublin 8, IrelandMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin D09 NR58, IrelandMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin D09 NR58, IrelandInstitute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Woolloongabba QLD 4059, AustraliaMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin D09 NR58, IrelandUCD School of Medicine, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, IrelandMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin D09 NR58, IrelandMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin D09 NR58, IrelandIn pre-clinical studies, triple-negative breast cancer (TNBC) cells have demonstrated sensitivity to the multi-targeted kinase inhibitor dasatinib; however, clinical trials with single-agent dasatinib showed limited efficacy in unselected populations of breast cancer, including TNBC. To study potential mechanisms of resistance to dasatinib in TNBC, we established a cell line model of acquired dasatinib resistance (231-DasB). Following an approximately three-month exposure to incrementally increasing concentrations of dasatinib (200 nM to 500 nM) dasatinib, 231-DasB cells were resistant to the agent with a dasatinib IC<sub>50</sub> value greater than 5 μM compared to 0.04 ± 0.001 µM in the parental MDA-MB-231 cells. 231-DasB cells also showed resistance (2.2-fold) to the Src kinase inhibitor PD180970. Treatment of 231-DasB cells with dasatinib did not inhibit phosphorylation of Src kinase. The 231-DasB cells also had significantly increased levels of p-Met compared to the parental MDA-MB-231 cells, as measured by luminex, and resistant cells demonstrated a significant increase in sensitivity to the c-Met inhibitor, CpdA, with an IC<sub>50</sub> value of 1.4 ± 0.5 µM compared to an IC<sub>50</sub> of 6.8 ± 0.2 µM in the parental MDA-MB-231 cells. Treatment with CpdA decreased p-Met and p-Src in both 231-DasB and MDA-MB-231 cells. Combined treatment with dasatinib and CpdA significantly inhibited the growth of MDA-MB-231 parental cells and prevented the emergence of dasatinib resistance. If these in vitro findings can be extrapolated to human cancer treatment, combined treatment with dasatinib and a c-Met inhibitor may block the development of acquired resistance and improve response rates to dasatinib treatment in TNBC.https://www.mdpi.com/2072-6694/11/4/548Src kinasebasal-like breast cancercMet |
| spellingShingle | Patricia Gaule Nupur Mukherjee Brendan Corkery Alex J. Eustace Kathy Gately Sandra Roche Robert O’Connor Kenneth J. O’Byrne Naomi Walsh Michael J. Duffy John Crown Norma O’Donovan Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells Cancers Src kinase basal-like breast cancer cMet |
| title | Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells |
| title_full | Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells |
| title_fullStr | Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells |
| title_full_unstemmed | Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells |
| title_short | Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells |
| title_sort | dasatinib treatment increases sensitivity to c met inhibition in triple negative breast cancer cells |
| topic | Src kinase basal-like breast cancer cMet |
| url | https://www.mdpi.com/2072-6694/11/4/548 |
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