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Cancers 2019, 11(4), 548;

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

Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin D09 NR58, Ireland
Trinity Translational Medicine Institute, St. James’s Hospital Dublin, Dublin 8, Ireland
Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Woolloongabba QLD 4059, Australia
UCD School of Medicine, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland
UCD Clinical Research Centre, St. Vincent’s University Hospital, Dublin 4, Ireland
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)
PDF [2168 KB, uploaded 17 April 2019]


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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