Fig. 1. PARPi and MEKi induce inverse adaptive responses.

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Fig. 1. PARPi and MEKi induce inverse adaptive responses. PARPi and MEKi induce inverse adaptive responses. (A) Ten breast, ovarian, and endometrial cell lines [BT474 (PIK3CA_Mut, HER2_Amp), HCC1954 (PIK3CA_Mut and HER2_Amp), HCC1937 (BRCA1_Mut), MDA-MB-468 (EGFR_Overexpression and PTEN_Mut), IGROV-1 (BRCA1_Mut), TOV21G (PIK3CA_Mut and KRAS_Mut), KLE (TP53_Mut), ETN-1 (PTEN_Mut), SKBr3 (HER2_Amp), SKOV3 (PIK3CA_Mut and HER2_Amp)] were cultured in Matrigel (3D) or monolayer (2D) and treated for 7 or 3 days, respectively, with DMSO or BMN673 at a median inhibitory concentration (IC50) determined experimentally for each line for 2D and 3D conditions. Protein lysates were analyzed for 220 total and phosphoproteins by RPPA. For visualization, 2D and 3D conditions and time were averaged (see fig. S1 for all samples). Heat map represents “rank-ordered” changes induced by BMN673 treatment, calculated by summing median-centered protein amount normalized to control. Proteins with consistent decreases are at the top (green) and increases are at the bottom (red) of the heat map. (B) Five cell lines from (A) (MDA-MB-468, HCC1954, BT474, SKOV3, and SKBr3) were cultured in Matrigel (3D) or monolayer (2D) and treated with MEKi (GSK1120212B) at two concentrations (2 and 20 nM) or DMSO for 24 or 48 hours, after which protein lysates were analyzed for 220 total and phosphoproteins by RPPA. (C) The left column of the heat map shows protein changes ordered by the effects of BMN673 treatment from (A), sorted in increasing order from top to bottom (green indicates the most consistently decreased proteins, and red indicates the most consistently increased proteins after treatment). The right column in the heat map shows protein order after GSK1120212B treatment from (B). (D) Comparison (2 × 2) of selected proteins [marked in (A) and (B)] after BMN673 and GSK1120212B treatment. Chaoyang Sun et al., Sci Transl Med 2017;9:eaal5148 Published by AAAS