Fig. 6. IKKβ inhibition is synthetic lethal to CDK12 inhibition in BRAF-mutated melanoma.

a Proliferation assays were performed in A375 (top) and Colo829 (bottom) cells treated with THZ531 at indicated doses, combined with BI605906 (10 µM) and MLN120B (20 µM) for 72 h. Respectively IC₅₀ concentration for A375 with THZ531 alone 224 nM, 40 nM and 53 nM in addition with BI605906 or MLN120B. IC₅₀ for Colo829 with THZ531 alone 162 nM, 65 nM and 57 nM in addition with BI605906 or MLN120B. Excess over Bliss synergy plots for serial dilutions of THZ531 in combination with BI605906 (b) or MLN120B (c) in A375 (top) and Colo829 (bottom) cells. Bliss scores >10 indicate drug synergy. Viability was assessed by WST1 (top) and Annexin-V (bottom) assay was performed in melanocytes (d), A375 (e) and Colo829 (f) cells. For WST1, THZ531 (100 nM) was combined with BI605906 (10 µM) and MLN120B (20 µM) for 72 h. For Annexin-V, THZ531 (100 nM) was combined with BI605906 (20 µM) and MLN120B (40 µM) for 48 h. Colony formation assays were performed in A375 cells treated with THZ531 (100 nM) combined with (g) BI605906 (10 µM) and (h) MLN120B (20 µM), for 21 days. Representation of colony formation assay (left) and quantification (right). Data are represented as mean ± SD of independent experiment, n = 5 (a), n = 5 for WST1 (d–f), n = 3 for Annexin-V (d–f) and n = 3 (g, h). Significance was determined using unpaired two-tailed Student’s t-tests. Source data are provided as a Source Data file.