Fig. 1

Study outline of kinase inhibitor screening. Three BRAF mutated melanoma cell lines, A375, IGR37 and 501Mel (each one in its parental (P), Vemurafenib (XP)- and Dabrafenib (GP)-resistant form) were treated with 2 concentrations (1 and 10 μM) of 274 different kinase inhibitors. 40 promising candidates were further characterized in dose-response assays, which led to the identification of 14 compounds that were used in combination treatments where synergism was assessed. Short- and long-term effects of combinations with 8 successful drugs were analyzed: Danusertib (Aurora kinase, FGFR, Bcr-Abl, c-RET, Src inhibitor), MK-1775 (Wee1 inhibitor), AZD7762 (Chk inhibitor), AZD8330 (MEK inhibitor), CHIR-124 (Chk inhibitor), Volasertib (Plk inhibitor), PIK-75 (PI3K, DNA-PK inhibitor), TAE226 (FAK inhibitor). BRAFi: BRAF inhibitor, Vemurafenib or Dabrafenib