MEK1/2-ERK1/2-p190RHOGAP and INK4a/ARF deficiency drive RHOA activation in NSCLC. A and B, G-LISA assay showing RHOA-GTP levels in H460, A549, and H838.

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MEK1/2-ERK1/2-p190RHOGAP and INK4a/ARF deficiency drive RHOA activation in NSCLC. A and B, G-LISA assay showing RHOA-GTP levels in H460, A549, and H838 NSCLC cells transduced as indicated. MEK1/2-ERK1/2-p190RHOGAP and INK4a/ARF deficiency drive RHOA activation in NSCLC. A and B, G-LISA assay showing RHOA-GTP levels in H460, A549, and H838 NSCLC cells transduced as indicated. O.D., optical density. Mean and SEM. *, P < 0.05; **, P < 0.004; n = 3. Wt, wild type. C, G-LISA assay showing RHOA-GTP levels (top) and immunoblot (bottom) in H292 cells transduced with the indicated retroviral vectors. Mean and SEM. **, P < 0.003; n = 3. D, immunoblot of H460 and A549 NSCLC cells treated with the indicated MEK1/2 inhibitors for 24 h. UO, UO126; ARRY, ARRY-142886. RHOA-GTP and RAC1-GTP were determined by GST-RBD and GST-PAK1 pulldown respectively. E, G-LISA assay showing RhoA-GTP levels of lung tumor lysates from KrasG12D;Ink4a/Arf−/− mice (after 12 weeks of KrasG12D induction) treated with ARRY-142886. The inhibitor was given 3 times (every 12 hours) and the mice were sacrificed 2 hours after the last treatment. Mean and SEM. ***, P < 0.001; n = 3. F, immunoblot showing p-Erk1/2 inhibition upon treatment with ARRY-142886. Each lane represents a lysate from a single mouse. G, GST-RBD pulldown for RHOA-GTP from (D), followed by immunoblot for p190RHOGAP in A549 cells treated as indicated. The ratio value between p190RHOGAP from pulldown and input is indicated. H, G-LISA assay showing RHOA-GTP levels (top) and immunoblot (bottom) in A459 cells after siRNA for p190A and/or 10 μmol/L UO126 treatment. p190A, p190RHOGAP. Georgia Konstantinidou et al. Cancer Discovery 2013;3:444-457 ©2013 by American Association for Cancer Research