Fig. 4: A chemical genetics screen revealed that inhibitors of the PIM kinases reverse the resistance of G-R cells to ipatasertib.

a Bar plot depicts average mean viability difference between G-R and Par cells (Avg Delta MV) of the chemical genetics screen hits. Compounds with Avg Delta MV ≤  −0.10 are plotted in ascending order. Compound targets are indicated above bar plot. Colors correspond to pathways targeted by each compound as indicated in legend. The mean Delta MV of all compounds screened is −0.01 (see also Supplementary Dataset 5). b Response of Par cells plated in DMSO-control medium or G-R cells plated in 5 μM ipatasertib-containing medium to the PIMi GNE-1571 was assessed using a 4-day viability assay. Error bars represent SEM; n = 4 replicates. c As in b except all cells were plated in DMSO-control medium. d Heatmaps depict % viability inhibition, Bliss or HSA scores associated with each dose combination treatment of Par or G-R3 cells with ipatasertib and PIMi (GNE-1571 or GDC-0339). Mean Bliss sum values from independent biological replicates are depicted in scatter plots below. Data are presented as Mean ± SD of the indicated numbers of biological replicates. e Indicated proteins were assessed by immunoblot following a 24-hour treatment with the indicated concentrations of ipatasertib and/or 0.1 μM GDC-0339 in Par or G-R3 cells. Representative data from at least 2 independent experiments are shown. See also Supplementary Figs. 6–9 and Supplementary Dataset 5. Source data are provided as a Source Data file.