| Literature DB >> 30833752 |
Kirsten L Bryant1, Clint A Stalnecker1, Daniel Zeitouni1, Jennifer E Klomp1, Sen Peng2, Andrey P Tikunov3, Venugopal Gunda4, Mariaelena Pierobon5, Andrew M Waters1, Samuel D George1, Garima Tomar1, Björn Papke1, G Aaron Hobbs1, Liang Yan6, Tikvah K Hayes7, J Nathaniel Diehl7, Gennifer D Goode4, Nina V Chaika4, Yingxue Wang8, Guo-Fang Zhang8, Agnieszka K Witkiewicz9, Erik S Knudsen10, Emanuel F Petricoin5, Pankaj K Singh4, Jeffrey M Macdonald3, Nhan L Tran11, Costas A Lyssiotis12, Haoqiang Ying6, Alec C Kimmelman13, Adrienne D Cox1,14,15, Channing J Der16,17,18.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth, but the role of KRAS in supporting autophagy has not been established. We show that, to our surprise, suppression of KRAS increased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. We speculated that ERK inhibition might thus enhance PDAC dependence on autophagy, in part by impairing other KRAS- or ERK-driven metabolic processes. Accordingly, we found that the autophagy inhibitor chloroquine and genetic or pharmacologic inhibition of specific autophagy regulators synergistically enhanced the ability of ERK inhibitors to mediate antitumor activity in KRAS-driven PDAC. We conclude that combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition may be effective treatments for PDAC.Entities:
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Year: 2019 PMID： 30833752 PMCID： PMC6484853 DOI： 10.1038/s41591-019-0368-8
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440