@article{9bf5b19c239f4bc083007579d60a473c,
title = "Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer",
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.",
author = "Bryant, {Kirsten L.} and Stalnecker, {Clint A.} and Daniel Zeitouni and Klomp, {Jennifer E.} and Sen Peng and Tikunov, {Andrey P.} and Venugopal Gunda and Mariaelena Pierobon and Waters, {Andrew M.} and George, {Samuel D.} and Garima Tomar and Bj{\"o}rn Papke and Hobbs, {G. Aaron} and Liang Yan and Hayes, {Tikvah K.} and Diehl, {J. Nathaniel} and Goode, {Gennifer D.} and Chaika, {Nina V.} and Yingxue Wang and Zhang, {Guo Fang} and Witkiewicz, {Agnieszka K.} and Knudsen, {Erik S.} and Petricoin, {Emanuel F.} and Singh, {Pankaj K.} and Macdonald, {Jeffrey M.} and Tran, {Nhan L.} and Lyssiotis, {Costas A.} and Haoqiang Ying and Kimmelman, {Alec C.} and Cox, {Adrienne D.} and Der, {Channing J.}",
note = "Funding Information: 70-25-BRYA). C.A.S. was supported by NCI T32CA009156 and F32CA232529. J.E.K. was supported by NCI T32CA009156 and F32 CA239328. A.M.W. was supported by American Cancer Society fellowship PF-18-061. B.P. was supported by the Deutsche Forschungsgemeinschaft (DFG PA 3051/1-1). G.A.H. was supported by NCI T32CA009156 and F32CA200313. T.K.H. was supported by NCI T32CA071341 and NCI F3180693. J.N.D. was supported by NCI T32CA071341. P.K.S. was supported by NCI grants R01 CA163649, R01 CA210439, R01 CA216853, and P30CA036727. A.C.K. was supported by NCI grants R01CA157490, R01CA188048 and P01CA117969, American Cancer Society Research Scholar Grant RSG-13-298-01-TBG, National Institutes of Health grant R01GM095567 and a grant from the Lustgarten Foundation. The Microscopy Services Laboratory, the UNC Flow Cytometry Core Facility and the Lenti-shRNA Core Facility (UNC) are supported in part by P30 CA016086 Cancer Center Core Support grant to the UNC Lineberger Comprehensive Cancer Center. Transmission electron microscopy was conducted in the High-Resolution Electron Microscopy Facility of the MD Anderson Cancer Center (supported by NIH P30CA016672). Funding Information: We thank A. Maitra (MD Anderson Cancer Center) for PDAC cell lines, D. Tuveson (Cold Spring Harbor Laboratory) for patient-derived organoids, and C. Kinsey and M. McMahon (Huntsman Cancer Center) for helpful discussions and communication of data before publication. K.L.B. is thankful to B. Elzer Jr. for continued inspiration. Support was provided by grants from the National Cancer Institute (NCI) (R01CA42978, R01CA175747, U01CA199235, P50CA196510, P01CA203657 and R35CA232113), the Department of Defense (W81XWH-15-1-0611), the Lustgarten Foundation (388222) and the Pancreatic Cancer Action Network/American Association for Cancer Research (AACR) (15-90-25-DER) (C.J.D. and A.D.C.). K.L.B. was supported by NCI T32CA009156 and a grant from the Pancreatic Cancer Action Network/AACR (15- Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = apr,
day = "1",
doi = "10.1038/s41591-019-0368-8",
language = "English (US)",
volume = "25",
pages = "628--640",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "4",
}