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

Publication ,  Journal Article
Bryant, KL; Stalnecker, CA; Zeitouni, D; Klomp, JE; Peng, S; Tikunov, AP; Gunda, V; Pierobon, M; Waters, AM; George, SD; Tomar, G; Papke, B ...
Published in: Nat Med
April 2019

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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Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

April 2019

Volume

25

Issue

4

Start / End Page

628 / 640

Location

United States

Related Subject Headings

  • Proto-Oncogene Proteins p21(ras)
  • Protein Kinase Inhibitors
  • Pancreatic Neoplasms
  • Mutation
  • Mitochondria
  • Mice
  • MAP Kinase Signaling System
  • Immunology
  • Humans
  • HEK293 Cells
 

Citation

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Bryant, K. L., Stalnecker, C. A., Zeitouni, D., Klomp, J. E., Peng, S., Tikunov, A. P., … Der, C. J. (2019). Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat Med, 25(4), 628–640. https://doi.org/10.1038/s41591-019-0368-8
Bryant, Kirsten L., Clint A. Stalnecker, Daniel Zeitouni, Jennifer E. Klomp, Sen Peng, Andrey P. Tikunov, Venugopal Gunda, et al. “Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer.Nat Med 25, no. 4 (April 2019): 628–40. https://doi.org/10.1038/s41591-019-0368-8.
Bryant KL, Stalnecker CA, Zeitouni D, Klomp JE, Peng S, Tikunov AP, et al. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat Med. 2019 Apr;25(4):628–40.
Bryant, Kirsten L., et al. “Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer.Nat Med, vol. 25, no. 4, Apr. 2019, pp. 628–40. Pubmed, doi:10.1038/s41591-019-0368-8.
Bryant KL, Stalnecker CA, Zeitouni D, Klomp JE, Peng S, Tikunov AP, Gunda V, Pierobon M, Waters AM, George SD, Tomar G, Papke B, Hobbs GA, Yan L, Hayes TK, Diehl JN, Goode GD, Chaika NV, Wang Y, Zhang G-F, Witkiewicz AK, Knudsen ES, Petricoin EF, Singh PK, Macdonald JM, Tran NL, Lyssiotis CA, Ying H, Kimmelman AC, Cox AD, Der CJ. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat Med. 2019 Apr;25(4):628–640.

Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

April 2019

Volume

25

Issue

4

Start / End Page

628 / 640

Location

United States

Related Subject Headings

  • Proto-Oncogene Proteins p21(ras)
  • Protein Kinase Inhibitors
  • Pancreatic Neoplasms
  • Mutation
  • Mitochondria
  • Mice
  • MAP Kinase Signaling System
  • Immunology
  • Humans
  • HEK293 Cells