Abstract Cancer cells utilize multiple scavenging mechanisms to support growth in nutrient-poor, hypoxic environments. Signaling pathways to accommodate these mechanisms may not be required for oncogenesis per se but are crucial for cancer cell survival. These processes, known as non-oncogene addiction, can be conferred by specific oncogenes that reprogram metabolism or by the tumor microenvironment. Understanding how these pathways are regulated can provide novel opportunities for therapeutic intervention. Studies showed that KRAS-mutant cancer cells, including pancreatic ductal adenocarcinoma (PDAC), upregulate macropinocytosis, a caveolin- and clathrin-independent endocytic process, to import extracellular protein to support growth upon nutrient depletion. Similarly, high levels of macropinocytic uptake are observed in PDAC murine models and also in human PDAC specimens. This process serves as a scavenging mechanism for cancer cells to survive and proliferate in nutrient-deprived tumor microenvironments. Thus, uncovering the key players of this pathway and the mechanisms underlying their regulation will be important to find potential therapeutic targets. Here, we used the Informer set of small molecules to screen regulators of survival in culture conditions supplemented with either glutamine or extracellular protein. The Informer set drug library consists of small molecules including FDA-approved drugs and clinical candidates that have high selectivity for their targets and regulate many cellular pathways. We find that survival of cells grown in conditions supplemented with glutamine or exogenous protein is differentially regulated by distinct drug subsets. This suggests that different pathways of nutrient uptake, processing, and utilization are used in cells depending on the nutrient source. Further examination to determine the mechanism of pathway inhibition and applicability may unravel potential uses for therapeutics. Citation Format: Sung Eun Kim, Man-Tzu Wang, Frank McCormick. Regulation of macropinocytosis-dependent cell survival in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 435. doi:10.1158/1538-7445.AM2017-435