Fig. 1

Tyrosine kinase inhibitors synergize with THZ531 to halt TNBC proliferation. A Proliferative response upon treatment with dose range of lapatinib in combination with transcriptional CDK inhibitors PHA-767491 (0.316 and 1 µM), CDKI-73 (0.1 and 0.316 µM), BAY-1143572 (0.1 and 0.316 µM), THZ1 (0.0316 and 0.1 µM), THZ531 (0.0316 and 0.1 µM) and SR4835 (0.01 and 0.0316 µM) in Hs578T. Data are the mean (± SD) of three independent experiments. B Corresponding mean bliss synergy scores of these CDK inhibitors with lapatinib, in Hs578T, SKBR7 and MDA-MB-231. C Proliferative responses in kinase inhibitor (KI) screening upon treatment with tyrosine (red) or other (blue) KI’s only (1 µM) or in combination with THZ531 (0.1 µM) in Hs578T. Data are the mean of two independent experiments. D Overlap between synergistic hits with more than 25 percentage point (pp) difference between the combined and additive effects of THZ531 (0.1 µM) and kinase inhibitors (1 µM) in Hs578T and MDA-MB-231 (upper). Overlap between synergistic hits in combination treatment with THZ531 (0.1 µM, 25 pp synergy) and THZ1 (0.0316 µM, 15 pp synergy) (lower). E Proliferation upon treatment with dose ranges of nilotinib, rabusertib, erlotinib, momelotinib, ralimetinib alone or in combination with THZ531 (0.1 µM) in Hs578T. Data are the mean (± SD) of four independent experiments. F, G Representative images (F) and percentages (G) of FUCCI cell cycle progression 24 h after treatment with lapatinib (3.16 µM), nilotinib, rabusertib, erlotinib, momelotinib and ralimetinib (all 1 µM) alone or in combination with THZ531 (0.1 µM) and single treatment of high dose THZ531 (1 µM) or cisplatin (10 µg/mL). H Induction of (apoptotic) cell death measured by Annexin V and PI staining after 24 h and 72 h of treatment with these inhibitors. Cell death and FUCCI data are the mean (± SD) of three independent experiments