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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • April 2019

Published In

Volume / Issue

  • 25 / 4

Start / End Page

  • 628 - 640

PubMed ID

  • 30833752

Pubmed Central ID

  • 30833752

Electronic International Standard Serial Number (EISSN)

  • 1546-170X

Digital Object Identifier (DOI)

  • 10.1038/s41591-019-0368-8

Language

  • eng

Conference Location

  • United States