Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer
Authors: Samuel D George
Alec C Kimmelman
Agnieszka K Witkiewicz
Yingxue Wang
Mariaelena Pierobon
Tikvah K Hayes
Venugopal Gunda
Emanuel F Petricoin 3rd
G Aaron Hobbs
Nina V Chaika
Jeffrey M Macdonald
Jennifer E Klomp
Andrew M Waters
Haoqiang Ying
Daniel Zeitouni
Kirsten L Bryant
Adrienne D Cox
Pankaj K Singh
Gennifer D Goode
Erik S Knudsen
Costas A Lyssiotis
Guo-Fang Zhang
Liang Yan
Nhan L Tran
Garima Tomar
J Nathaniel Diehl
Channing J Der
Sen Peng
Andrey P Tikunov
Björn Papke
Clint A Stalnecker
Journal: Nature Medicine (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Pancreatic ductal adenocarcinoma; KRAS; autophagy; tumorigenic growth; ERK MAPK
Affiliations: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA., Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA., Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA, USA., Department of Molecular and Cellular Oncology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC, USA., Center for Personalized Medicine, Roswell Park Cancer Center, Buffalo, NY, USA., Department of Molecular and Cell Biology, Roswell Park Cancer Center, Buffalo, NY, USA., Department of Cancer Biology, Mayo Clinic, Phoenix, AZ, USA., Department of Molecular and Integrative Physiology; Department of Internal Medicine, Division of Gastroenterology and University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA., Perlmutter Cancer Center, NYU Langone Medical Center, New York City, NY, USA., Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ., Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ., Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. .

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. 

Retracted: No

PubPeer comments:
 Authors should check the MM panel of Figure 1b and DMSO panel of Figure 2h , 
 #1 I agree these look very similar. 1b (left) and 2h (right). ***![file] , 
 We reported this to Nature Medicine in October 2019 and provided a correction for the figure. An erratum should have been published, but was not. We have followed up with Nature Medicine to determine what the situation is with publishing our erratum. , 
 Correction to: Nature Medicine https: doi.org 10.1038 s41591-019-0368-8, published online 4 March 2019. In the version of this article initially published, in Fig. 1b, the MM control images for HPAF-II incorrectly displayed duplicates of the BxPC-3 DMSO control images from Fig. 2h, and in Extended Data Fig. 2a, the color-coding of the u2018basalu2019 and u2018CQu2019 bars for the Pa04C cell line, DMSO condition, was erroneously switched. The errors have been corrected in the HTML and PDF versions of the article. ![file] ,