Pancreatic ductal adenocarcinoma (PDA) was responsible for ~43,000 deaths in the USA in 2017 and is the quintessential recalcitrant cancer driven by a pharmacologically intractable oncoprotein, KRAS. Although the clinical picture remains grim, the mechanisms by which key alterations in tumor suppressors and proto-oncogenes contribute to PDA have been dissected. Downstream of KRAS, the RAF→MEK→ERK signaling pathway plays a central role in pancreatic carcinogenesis. However, to date, pharmacological inhibition of this pathway has provided no clinical benefit to PDA patients. Recently we have shown that inhibition of KRAS→RAF→MEK→ERK signaling in PDA cell lines elicits autophagy, a process of cellular recycling that protects pancreatic cancer cells from the potentially cytotoxic effects of KRAS pathway inhibition. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic anti-proliferative effects against PDA cell lines in vitro, and promotes regression of xenografted patient-derived PDA tumors in mice. These observations are not limited to pancreatic cancer as similar findings have been made in NRAS-mutated melanoma and in KRAS-mutated lung cancer. Finally, treatment of a PDA patient with the combination of trametinib plus hydroxychloroquine (T/HCQ) resulted in a partial, but nonetheless striking disease response. These data suggest that this combination therapy may represent a new strategy to target RAS-driven cancers such as PDA