Combination of MEK and autophagy inhibition promotes tumor regression in the KPC mouse model of pancreatic cancer

Abstract Activating mutations of Kras are the main genetic drivers of pancreatic ductal adenocarcinoma (PDA) and are essential for its initiation and maintenance. It was recently shown that suppression of the Kras effectors Raf/Mek/Erk in the context of Kras-mutant pancreatic tumors leads to the increase of autophagic flux, suggesting that this inhibition may be enhancing PDA dependence on autophagy. Autophagy, a lysosome-mediated process, allows cells to degrade organelles and macromolecules and recycle the intermediates to sustain cell metabolism, critical for tumor growth. This discovery, made recently by two independent research teams, led to the development of a two-drug regimen that blocks MEK/ERK and autophagy pathways and produces consistent synergistic responses in cell lines, in several transplantation models, and in a human PDA patient. Here we present results from an intervention study performed in the K-rasLSL.G12D/+, p53LSL.R172H/+, Pdx1Cre (KPC) mice, a highly chemoresistant genetically engineered model of PDA. We found that a two-drug regimen of trametinib (MEK inhibitor) and hydroxychloroquine (autophagy inhibitor) induced frank regressions in all six animals treated to date—an unmatched response in this model. Tumor regressions ranging from 30% to 95% following treatment were sizable, as measured by longitudinal 3D high-resolution ultrasound, and these mice survived significantly longer than historical controls treated with saline under identical conditions. IHC performed on tumor tissues from treated mice showed decreased proliferation and increased apoptosis relative to untreated KPC pancreatic tumors. Some tumors exhibited substantially reduced phospho-ERK expression by IHC. Interestingly, some tumors that underwent large regressions exhibited positive staining for phospho-ERK in the residue tumor tissues, suggesting a mechanism of resistance through the reactivation of this downstream effector. Studies focused on mechanisms of acquired resistance are ongoing. Citation Format: Urszula N. Wasko, Stephen A. Sastra, Carmine F. Palermo, Kenneth P. Olive. Combination of MEK and autophagy inhibition promotes tumor regression in the KPC mouse model of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C60.