Identification of a Triple Drug Combination That Is Synergistically Cytotoxic for Triple-Negative Breast Cancer Cells Using a Novel Combination Discovery Approach

Abstract

Triple-negative breast cancer (TNBC) is a very aggressive form of breast cancer with few molecularly targeted therapies. We used a novel unbiased approach to identify higher-order synergistic or enhancer combinations of marketed kinase inhibitor drugs that inhibit cell viability of TNBC cell lines. We mixed all 33 kinase-targeted drugs on the market at the time of this study, which allowed for all possible combinations to exist in the initial mixture. A kinase inhibitor group dropout approach was used to identify active groups and then single active drugs. After only three rounds of deconvolution, we identified five single drugs to test further. After further testing, we focused on one novel subset consisting of three kinase inhibitor drugs: dasatinib, afatinib, and trametinib (DAT) that target src family kinases, HER2/EGFR, and MEK, respectively. The DAT combination potently inhibited the proliferation of three TNBC cell lines and modestly inhibited a fourth. However, it was not significantly more potent or synergistic than other two drug combinations of these drugs. The cytotoxic activities of all possible combinations of these three drugs were also analyzed. Compared with all two-way combinations, the three-way DAT combination generated the most cytotoxicity and the highest synergies for two of the four cell lines tested, with possibly mild synergy in a third cell line. These data indicated that the DAT combination should be evaluated for efficacy in an in vivo model of TNBC and may provide a novel combination of existing drugs for the treatment of a subset of TNBC cases.

Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer

“…A combination screening of 33 FDA-approved PKIs identified a triple combination of afatinib, dasatinib, and trametinib as an effective strategy for TNBC treatment [ 444 ]. The drug combination discovery approach was designed to use a single-mixture solution of 33 PKIs at the start and then to use dropout solutions in the TNBC cell line HCC1143.…”

“…The triple combination displayed antiproliferative activity in two TNBC cell lines, HCC1143 and MDA-MB-468. Although the mechanism of action remains to be investigated, the results suggest that simultaneous inhibition of the PI3K/AKT and MEK/ERK pathways is a promising approach to potentiate EGFRis in TNBC [ 444 ].…”

Successful use of trametinib and dasatinib combined with chemotherapy in the treatment of Ph-positive B-cell acute lymphoblastic leukemia

“…In our case, we demonstrated that the drug combination did not display any significant enhancement of cytotoxic activity compared with dasatinib alone. [ 18 ] After including trametinib in the treatment regimen, WBC and ANC remained above 3 × 10 9 /L and 0.5 × 10 9 /L, respectively, more frequently than before introducing the drug (77% vs 83% and 72% vs 83%, respectively); this may be related to an infection fever just before trametinib treatment. The mean values of glutamic amino transferase, aspartic amino transferase, and creatinine were slightly higher after the combined treatment with trametinib, while those of urea were similar.…”

Drug combination and repurposing for cancer therapy: the example of breast cancer

“…Recently, three kinase inhibitors: dasatinib, afatinib, and trametinib (DAT) potently stopped the proliferation of TNBC (Triple Negative Breast Cancer) cell lines. These experiments may provide evidence for a novel combination module for the treatment of breast cancer, in particular the triple negative form, the most aggressive [ 48 ]. Also, a promising combination of drugs for TNBC is the combination of auranofin and vitamin C, presenting a redox-based anticancer activity [ 49 ].…”