To address the necessity for new therapeutic targets, we have taken a multipronged approach to identify molecular signatures associated with NF1 loss. Using a panel of pairs of NF1-deficient (NF1-/-) and normal type (NF1-/+) isogenic patient-derived or CRISPR-edited NF1-deficient SCs, we conducted profiling of the activated kinome, total and phosphoproteome, and transcriptome signatures. We have identified several kinases with altered activity, proteins with altered phosphorylation patterns, and genes with altered transcription levels. We performed comparison analyses between two isogenic sets of patient-derived SCs to identify overlapping hits, and in doing so, we were able to refine our list of potential targets. Finally, by combining our data sets we used network analysis to identify pathways with increased activity based on changes between NF1-/- and NF1-/+ SC lines. We hypothesize that further interrogation and perturbation of signaling networks identified as altered between NF1-/- and NF1-/+ cells will reveal novel therapeutic targets for treating NF1-deficient tumors.