Fig. 6

Tyrosine kinase inhibitors sensitize Hs578T cells to intronic polyadenylation induction by THZ531. A Gene track example of the SOS1 gene from RNA sequencing data upon 8 h treatment with THZ531 (0.1 µM), lapatinib (3.16 µM), nilotinib (1 µM), a combination thereof, and high dose THZ531 (1 µM), showing intronic polyadenylation (IPA) for the combination treatments and high dose THZ531. B Quantification of differential exon expression (Log2 FC) downstream and upstream of the IPA site, blue dots indicate genes with significantly downregulated exons downstream of (after) the IPA site compared to upstream of (before) the IPA site (difference Log2 FC before and after > 0.75, adjusted p values of exons after IPA < 0.01). C Quantification of differential expression (Log2 FC and Adjusted p value) of the IPA site itself, blue dots indicate significantly increased expression of IPA sites (adjusted p < 0.001, Log2 FC > 1). D Presentation of significant IPA events (blue) showing events that had a significantly decreased exon expression downstream of the IPA site and had significantly increased expression of the IPA site itself. E Number of genes with significant IPA events upon treatment with the different conditions. F Overlap of genes with significant IPA events in the combination treatments (Lapatinib/Nilotinib + THZ531 0.1 µM) versus high dose THZ531 (1 µM). G Log2 FC of exons upstream and downstream of the IPA site and of the IPA site of the top 40 genes with most strong IPA event after treatment with lapatinib and THZ531 (0.1 µM), sorted on lowest Log2 FC of exons after IPA site. H Illustration of mechanism of synergy between THZ531 and kinase inhibitors via ABCG2 transporter inhibition. Illustration was created with BioRender.com