Fig. 2

Kinase inhibitor combination screening identifies compounds which synergise with EGFR-TKIs in TNBC. a EGFRi lapatinib (Lap) and kinase inhibitor (KI) combination screen in EGFRi-resistant Hs578T cells. Cells (8000/well) were treated with 1 μM of 273 individual KIs alone, or in combination with lapatinib at 3.16 μM, for 4 days. The dual cdc7/CDK9 inhibitor PHA-767491, one of the KIs which most strongly synergised with lapatinib, is singled out, as indicated. b Dose response curves for Hs578T cells. Cells were treated with a dose range of PHA-767491 or lapatinib (0.0316–3.16 μM) or lapatinib combined with 0.316, 1 or 3.16 μM PHA-767491. Data shown as mean ± standard deviation for two independent experiments. c Validation screen of lapatinib/PHA-767491 synergistic effect in a panel of 17 TNBC cell lines, under indicated combinations. Cells were treated with dose ranges of lapatinib or PHA-767491 (0.0316–3.16 μM) or the indicated combinations. d Combination indices (CI) for lapatinib (3.16 μM) combined with either 1 μM or 3.16 μM PHA-767491. Log CI is shown. e Initiation of DNA replication and productive transcriptional elongation in Hs578T, BT549 and SKBR7 cells treated with lapatinib and/or PHA-767491 as indicated, for 48 h. TKI refers to lapatinib at 3.16 μM