Modulation of KRASG12C activity alters ARS-853 target engagement and supports novel therapeutic strategies for targeting KRAS. A, schematic for altering.

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Modulation of KRASG12C activity alters ARS-853 target engagement and supports novel therapeutic strategies for targeting KRAS. A, schematic for altering KRAS-GTP through growth factor or small molecule inhibitors. Modulation of KRASG12C activity alters ARS-853 target engagement and supports novel therapeutic strategies for targeting KRAS. A, schematic for altering KRAS-GTP through growth factor or small molecule inhibitors. B, RBD-MS analysis of H358 cells treated with erlotinib (2.5 μmol/L) harvested at the indicated time points. Experimental data values were used as input into the kinetic model parameters shown in Figure 4A (right). The fit estimates a GTP hydrolysis rate half-life on KRASG12C of 27 minutes. C, RBD-MS analysis of GTP-bound KRASG12C and WT-RAS (K/N/H isoforms) following pretreatment of H358 cells with EGF (100 ng/mL, 1 hour), erlotinib (2.5 μmol/L, 2 hours), or trametinib (100 nmol/L, 24 hours). Top, the formula used for calculating %RAS-GTP by the RBD-MS assay (see also Supplementary Fig. S6 for details). D, LC/MS-MS–based detection of KRASG12C target engagement by ARS-853 (10 μmol/L, 1 hour) in H358 cells treated with the indicated agent to alter the RAS-GTP fraction. Top, timing and design of pretreatment or cotreated conditions: trametinib (100 nmol/L) was added 24 hours prior, and erlotinib (2.5 μmol/L) 1 hour prior to ARS-853 addition, and EGF (100 ng/ml) was cotreated with ARS-853. #, P < 0.001 by ANOVA compared with ARS-853 treatment alone. ARS-853 cell engagement is modulated consistent with specific reactivity to GDP-bound KRASG12C. E, immunoblot experiment from biologic replicate lysates depicted in D. F, antiproliferative effects of ARS-853 treatment of H358 cells cultured with or without EGF (50 ng/mL) for 5 days. G, antiproliferative effects of combination treatments (0.4 μmol/L erlotinib, 0.1 μmol/L afatinib, or 50 nmol/L trametinib), on H358 cells cultured with or without EGF (50 ng/mL) for 5 days. H, immunoblot assessment KRAS signaling following 24 hours treatment of H358 cells with ARS-853 in combination with erlotinib (5 μmol/L), afatinib (100 nmol/L), or trametinib (100 nmol/L). Matthew P. Patricelli et al. Cancer Discov 2016;6:316-329 ©2016 by American Association for Cancer Research