Fig. 6.

Decreased ADAM activity via kinase inhibition mediates drug resistance. (A) The 24 h treatments with kinase inhibitors that target Mek (blue), Jnk (magenta), p38 (red), and PI3K (cyan) lead to reduced supernatant levels of ligands and RTKs (ELISA). Cells were also cotreated with EGF or mab225. (B) PrAMA-inferred sheddase activities decrease in response to 4 h Mek and Jnk inhibitor treatment. (C) NRG1b-induced p-HER2 increases following a 1.5 h pretreatment with Mek and Jnk inhibitors (bead immunoassay). (D) Mek and PI3K inhibitor efficacies depend on growth factor context, while Jnk and p38 inhibitors do not (24 h endpoint migration assay). (E) Data from D were combined with experiments using additional Jnk and Mek inhibitors, and results are plotted to highlight differences in inhibitor efficacy under EGF- vs. HGF/NRG1b-stimulated conditions. All error bars denote SE. (*P < 0.05, Student t test.)