Recent exome sequencing of pancreatic ductal adenocarcinoma (PDAC) determined that aside from the near 100% mutational activation of KRAS, no other oncoproteins are mutationally activated beyond single digit percentages. This has renewed interest in efforts to make undruggable K-Ras druggable. The most promising direction involves inhibitors of K-Ras effector signaling, prompting current clinical evaluation of the Raf-MEK- ERK cascade and the phosphatidylinositol 3-kinase (PI3K)-AKT-mTOR signaling network. However, to date, when applied as monotherapy, or with limited combination approaches, these inhibitors have shown little to no clinical efficacy for RAS mutant cancers. Two key issues contribute to this failure. First, kinome reprogramming mechanisms drive resistance mechanisms that reactivate the pathway downstream of the inhibitor block point. Second, it is clear that cancer cell dependency on mutant K-Ras cannot be attributed to the Raf and PI3K effectors alone, prompting efforts to validate noncanonical effectors for anti-K-Ras drug discovery. We propose that therapeutic targeting of the lesser studied Rac small GTPase effector pathway and its key effector, the Group I PAK serine/threonine kinases will address both issues. To accomplish this, we propose the application of three innovative tools to interrogate the role and mechanism by which the Rac-PAK effector network contributes to K-Ras-driven cancer growth. Specifically, our studies will focus on two immerging themes in signal transduction targeted therapies: (i) dynamic signal reprogramming mechanisms that drive de novo or acquired resistance to limit the therapeutic activity of signaling inhibitors and (ii) the cancer driver function of a signaling protein is strongly dependent on subcellular location. We have assembled a team of researchers with diverse and complementary expertise to (1) define the mechanisms of PAK1 activation by aberrant K-Ras- Rac1 signaling and the driver functions of plasma membrane-associated, cytoplasmic and nuclear PAK1, (2) identify the spatio-temporal phosphorylation events essential for aberrant PAK1 activation and PAK1- dependent cancer growth, (3) profile kinome reprogramming to identify the compensatory protein kinases that overcome PAK1 inhibition to promote cancer cell resistance, and (4) determine if Group I PAK suppression enhances PDAC sensitivity to inhibitors of the Raf or PI3K effector pathways.