Glioblastoma multiforme (GBM) is a deadly brain cancer for which survival outcomes have not significantly improved in decades. Several challenges exist for treatment of GBM related to anatomical location and molecular heterogeneity, as tumors are often comprised of mixed cellular populations with distinct oncogenic profiles arising during tumorigenesis and in response to therapy. These challenges have limited the effectiveness of targeted therapies designed to treat GBM tumors with specific proto-oncogenes or dysregulated signaling pathways, despite their clear pathological importance. To overcome these challenges, it will be important to identify targets broadly expressed across GBM that are invariant to heterogeneous oncogenic profiles. Additionally, combination therapies that co-target multiple populations, or exploit adaptive resistance mechanisms to monotherapy, will be necessary to robustly inhibit the spectrum of pathways essential to GBM phenotypes. Using both experimental and computational tools, this thesis identified combination approaches to improve targeted therapy response in GBM, primarily via interrogation of the cellular processes mediated by Sprouty2 and SHP2, two proteins which are particularly attractive targets based on their conserved expression across many GBM cell backgrounds. In the first example strategy, quantitative signaling measurements were used to identify that combined inhibition of the receptor tyrosine kinases (RTKs) EGFR, MET, and FGFR is necessary to durably suppress Sprouty2 expression, an important mediator of GBM cell survival to RTK inhibitors. In another example, data-driven statistical modeling revealed multiple unanticipated effects of SHP2 inhibition, one being that SHP2 antagonism promoted resistance to chemotherapy, cautioning against combining these treatments. Lastly, a suicide gene therapy developed as part of this thesis was used to target cells with elevated ERK activity, predicted to be particularly effective in combination with therapies conferring ERK-mediated resistance. In each example, the identified strategies were tested across multiple experimental models including differentiated cell lines, glioma-initiating cells, mouse xenografts, and human patient samples. Overall, this thesis improved understanding of signaling pathways controlling and controlled by Sprouty2 and SHP2, identified and tested novel combination treatment strategies based on this gained understanding, and developed diagnostic (i.e., in vivo reporter) and therapeutic (i.e., gene therapy) tools to improve targeted therapy response in GBM.