Fig. 5. JNK inhibition is synthetic lethal to CDK12 inhibition in BRAF-mutated melanoma.

a Proliferation assay was performed in A375 (top) and Colo829 (bottom) cells with THZ531 at indicated doses combined with AS601245 (5 µM) and JNK-in-8 (2 µM) for 72 h. Respectively IC₅₀ concentration for A375 with THZ531 alone 210 nM, 20 nM and 86 nM in addition with AS601245 or JNK-IN8. IC₅₀ for Colo829 with THZ531 alone 183 nM, 42 nM and 96 nM in addition with AS601245 and JNK-IN-8. b, c 3D synergy landscapes for serial dilutions of THZ531 and AS601245 (b) or JNK-IN-8 (c) combination in A375 (top) and Colo829 (bottom) cells. Representation of the Bliss synergy, Bliss scores >10 indicate drug synergy. Viability was assessed using WST1 (top) and Annexin-V (bottom) assays performed in melanocytes (d), A375 (e), and Colo829 (f) cells. For WST1, THZ531 (100 nM) was combined with AS601245 (1 µM) and JNK-IN-8 (2 µM) for 72 h. For Annexin-V, THZ531 (100 nM) was combined with AS601245 (5 µM) and JNK-IN-8 (3 µM) for 48 h. Colony formation assay was performed in A375 cells with THZ531 (100 nM) combined with (g) AS601245 (1 µM) and (h) JNK-IN-8 (1 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.