학술논문
Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer
Document Type
Article
Author
Bryant, Kirsten L.; Stalnecker, Clint A.; Zeitouni, Daniel; Klomp, Jennifer E.; Peng, Sen; Tikunov, Andrey P.; Gunda, Venugopal; Pierobon, Mariaelena; Waters, Andrew M.; George, Samuel D.; Tomar, Garima; Papke, Björn; Hobbs, G. Aaron; Yan, Liang; Hayes, Tikvah K.; Diehl, J. Nathaniel; Goode, Gennifer D.; Chaika, Nina V.; Wang, Yingxue; Zhang, Guo-Fang; Witkiewicz, Agnieszka K.; Knudsen, Erik S.; Petricoin, Emanuel F.; Singh, Pankaj K.; Macdonald, Jeffrey M.; Tran, Nhan L.; Lyssiotis, Costas A.; Ying, Haoqiang; Kimmelman, Alec C.; Cox, Adrienne D.; Der, Channing J.
Source
Nature Medicine; April 2019, Vol. 25 Issue: 4 p628-640, 13p
Subject
Language
ISSN
10788956; 1546170X
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 KRASincreased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate that either KRASsuppression 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.