Pancreatic cancer is the 4th leading cause of cancer deaths in the US and the 5-year survival rate is a dismal 6%. The KRAS oncogene is mutated in ~95% of pancreatic ductal adenocarcinoma (PDAC) and there is considerable experimental evidence that continued expression of mutant KRAS is essential for PDAC maintenance. In the 2013 Report to the Director of the NCI, the Pancreatic Cancer Working Group identified targeting KRAS as one of four key priorities for pancreatic cancer research. We hypothesize that inhibition of K-Ras effector signaling is the most promising approach to achieve this goal and that disrupting the Raf-MEK- ERK mitogen-activated protein kinase (MAPK) cascade will be key to accomplish this. Despite intensive research and clinical evaluation of the Raf-MEK-ERK pathway as a therapeutic approach for KRAS-mutant cancers, to date the results have been limited and disappointing. This does not mean that it is the wrong direction to take; rather we argue that effective combinations will be needed to block this pathway at multiple nodes, both to disrupt the feedback mechanisms that overcome inhibitor action and to disrupt resistance mechanisms that render cancer cells non-addicted to ERK signaling. Our studies determined that KRAS suppression in KRAS-mutant PDAC cell lines caused a severe growth defect that was associated with near- complete loss of Myc protein expression. Direct suppression of MYC alone phenocopied KRAS suppression and caused a severe growth defect, supporting MYC as a major driver of KRAS-dependent growth. Although previous studies identified ERK and AKT as mechanisms by which Ras effector signaling can regulate Myc degradation, our studies determined that, in PDAC, KRAS supports Myc protein stabilization by ERK- and AKT-independent signaling mechanisms. These observations provide the rationale for our Specific Aims to: (1) determine the role of Myc in KRAS-dependent pancreatic cancer growth, (2) determine the mechanisms of KRAS-dependent Myc protein stabilization, (3) assess specific Raf isoforms as therapeutic targets for PDAC treatment, and (4) determine mutation-specific differences in K-Ras effector signaling. Our studies pursue the provocative possibility that "the oncogene from hell", the Myc transcription factor, may ultimately be the Achilles' heel of otherwise "undruggable" Ras. We also revisit the issue of targeting Raf with second generation Raf inhibitors that do not suffer from the paradoxical activation of ERK. Here we will apply innovative chemical and genetic screens to identify combination approaches to achieve long-term suppression of Raf function. Finally we provide a critical test of the emerging yet untested concept that "not all Ras mutations are created equal", but instead that they utilize distinct effector functions and hence will require distinct therapeutic approaches. Collectively, our studies will address key priorities of the Ras Megaproject, with the goal of developing the long-elusive effective anti-K-Ras therapeutic approach for PDAC. PUBLIC HEALTH RELEVANCE: Effective signal-targeted therapies remain to be found for pancreatic cancer, the 4th leading cause of cancer deaths in the US. The near 100% frequency of KRAS mutations and its validated role as a driver of pancreatic growth argue that effective anti-KRAS therapies will provide successful treatments for this deadly cancer. We will take a comprehensive approach to understand KRAS dependency and to develop effective combinations of inhibitors of the key KRAS pathway, the Raf-MEK-ERK cascade, to target KRAS for pancreatic cancer treatment.