Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer

Nat Med. 2019 Apr;25(4):628-640. doi: 10.1038/s41591-019-0368-8.

Kirsten L Bryant ¹, Clint A Stalnecker ¹, Daniel Zeitouni ¹, Jennifer E Klomp ¹, Sen Peng ², Andrey P Tikunov ³, Venugopal Gunda ⁴, Mariaelena Pierobon ⁵, Andrew M Waters ¹, Samuel D George ¹, Garima Tomar ¹, Björn Papke ¹, G Aaron Hobbs ¹, Liang Yan ⁶, Tikvah K Hayes ⁷, J Nathaniel Diehl ⁷, Gennifer D Goode ⁴, Nina V Chaika ⁴, Yingxue Wang ⁸, Guo-Fang Zhang ⁸, Agnieszka K Witkiewicz ⁹, Erik S Knudsen ¹⁰, Emanuel F Petricoin 3rd ⁵, Pankaj K Singh ⁴, Jeffrey M Macdonald ³, Nhan L Tran ¹¹, Costas A Lyssiotis ¹², Haoqiang Ying ⁶, Alec C Kimmelman ¹³, Adrienne D Cox ¹ ¹⁴ ¹⁵, Channing J Der ¹⁶ ¹⁷ ¹⁸

Affiliations

1 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
2 Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
3 Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
4 Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA.
5 Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA, USA.
6 Department of Molecular and Cellular Oncology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
7 Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
8 Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC, USA.
9 Center for Personalized Medicine, Roswell Park Cancer Center, Buffalo, NY, USA.
10 Department of Molecular and Cell Biology, Roswell Park Cancer Center, Buffalo, NY, USA.
11 Department of Cancer Biology, Mayo Clinic, Phoenix, AZ, USA.
12 Department of Molecular and Integrative Physiology; Department of Internal Medicine, Division of Gastroenterology and University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
13 Perlmutter Cancer Center, NYU Langone Medical Center, New York City, NY, USA.
14 Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
15 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
16 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. cjder@med.unc.edu.
17 Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. cjder@med.unc.edu.
18 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. cjder@med.unc.edu.

PMID: 30833752 DOI: 10.1038/s41591-019-0368-8

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.

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HY-U00418

ARS-1620

99.62%, Ras Inhibitor

Ras

Cancer

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