Abstract IA12: Targeting KRAS-regulated metabolic activities in pancreatic cancer

Abstract

Abstract One promising direction for the development of therapeutic strategies for the treatment of KRAS-driven pancreatic ductal adenocarcinoma (PDAC) growth involves delineating the role of and mechanism for altered metabolism. KRAS-mutant PDAC is characterized by increased autophagy and macropinocytosis, processes that enhance nutrient availability that then supports the increased metabolic needs of PDAC. First, we addressed the role of KRAS in supporting autophagy-dependent PDAC growth. Surprisingly, we found that suppression of KRAS increased autophagic flux, as did pharmacologic inhibition of its effector ERK MAPK. We speculated that ERK inhibition might enhance PDAC dependence on autophagy by impairing KRAS-driven metabolic processes, and we demonstrate that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. Furthermore, genetic or pharmacologic inhibition of autophagy synergistically enhanced ERK inhibitor-mediated antitumor activity. We conclude that concurrent inhibition of ERK and autophagy may be an effective PDAC treatment. Second, we evaluated mechanisms by which KRAS may drive macropinocytosis. These studies focused on KRAS G12R mutant PDAC. This mutation is rare in lung and colorectal cancers (~1%), yet high (~20%) in PDAC. We evaluated whether KRAS G12R is functionally distinct from the more common KRAS G12D/V mutant proteins. We found that KRAS G12D/V but not KRASG12R drives elevated macropinocytosis and that MYC is essential for this process in KRAS G12D/V but not KRAS G12R mutant PDAC. The KRAS G12R mutation uniquely disrupts interaction with a key effector, PI3K alpha, due to structural perturbations in the switch II region critical for effector interaction. Despite this defect, KRAS G12R-mutant PDAC displayed elevated macropinocytosis due to KRAS-independent PI3K gamma activity. Finally, the growth of KRAS G12R mutant PDAC in vitro and in vivo was preferentially sensitive to MEK-ERK inhibition compared to KRAS G12D/V. In summary, our elucidation of KRAS-dependent effector signaling mechanisms that drive altered metabolism identified novel therapeutic approaches for the treatment of PDAC. Citation Format: Kirsten L. Bryant, G. Aaron Hobbs, Channing J. Der. Targeting KRAS-regulated metabolic activities in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA12.