Fig. 2

ABCG2 is associated with drug resistance and synergy with THZ531. A Bliss synergy scores for a panel of TNBC cell lines treated with a dose range of lapatinib and nilotinib, in combination with THZ531 0.0316 and 0.1 µM. Data are the mean (± SD) of two (MDA-MB-468, MDA-MB-436 and SUM159PT) or three (other cell lines) independent experiments. B Proliferative responses of TNBC cell line panel to a dose range of THZ531 alone. Lines are coloured by extent of synergy with lapatinib and nilotinib and THZ531 (blue, strong synergy; grey, modest synergy; red, weak synergy) C Schematic overview of CRISPR-Cas9 dropout screen for genes that sensitize Hs578T cells to THZ531 0.1 µM. This illustration was created with BioRender.com. D CRISPR-Cas9 dropout screening results showing median Log2 FC and corresponding FDR p value of gRNA levels in in Hs578T THZ531-treated pool versus DMSO. Orange dots present gene knockouts that were only affected upon THZ531 treatment, while red dots indicate gene knockouts that were also reduced in DMSO compared to T0. Data show the mean from three independent experiments and use the median Log2 FC of multiple different sgRNA’s per gene. E Rank-ordered microarray-based mRNA expression from gene set enrichment analysis of THZ531-resistant and synergistic cell lines versus THZ531-sensitive and non-synergistic cell lines showing the top and bottom 10 genes correlated with this phenotype