Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells
AbstractIn 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
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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.
Gaule P, Mukherjee N, Corkery B, Eustace AJ, Gately K, Roche S, O’Connor R, O’Byrne KJ, Walsh N, Duffy MJ, Crown J, O’Donovan N. Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells. Cancers. 2019; 11(4):548.Chicago/Turabian Style
Gaule, Patricia; Mukherjee, Nupur; Corkery, Brendan; Eustace, Alex J.; Gately, Kathy; Roche, Sandra; O’Connor, Robert; O’Byrne, Kenneth J.; Walsh, Naomi; Duffy, Michael J.; Crown, John; O’Donovan, Norma. 2019. "Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells." Cancers 11, no. 4: 548.
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