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Cancers 2019, 11(4), 548; https://doi.org/10.3390/cancers11040548

Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells

1
Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin D09 NR58, Ireland
2
Trinity Translational Medicine Institute, St. James’s Hospital Dublin, Dublin 8, Ireland
3
Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Woolloongabba QLD 4059, Australia
4
UCD School of Medicine, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland
5
UCD Clinical Research Centre, St. Vincent’s University Hospital, Dublin 4, Ireland
6
Department of Medical Oncology, St Vincent’s University Hospital, Dublin 4, Ireland
*
Author to whom correspondence should be addressed.
Received: 4 April 2019 / Accepted: 13 April 2019 / Published: 17 April 2019
(This article belongs to the Special Issue Treatment Strategies and Survival Outcomes in Breast Cancer)
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Abstract

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 IC50 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 IC50 value of 1.4 ± 0.5 µM compared to an IC50 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. View Full-Text
Keywords: Src kinase; basal-like breast cancer; cMet Src kinase; basal-like breast cancer; cMet
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Gaule, P.; Mukherjee, N.; Corkery, B.; Eustace, A.J.; Gately, K.; Roche, S.; O’Connor, R.; O’Byrne, K.J.; Walsh, N.; Duffy, M.J.; Crown, J.; O’Donovan, N. Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells. Cancers 2019, 11, 548.

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