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. Epub 2019 Mar 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Autophagy*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chloroquine / pharmacology*
  • Drug Synergism
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System* / drug effects
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mutation / genetics
  • Pancreatic Neoplasms / enzymology*
  • Pancreatic Neoplasms / pathology*
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism

Substances

  • KRAS protein, human
  • Protein Kinase Inhibitors
  • Chloroquine
  • Proto-Oncogene Proteins p21(ras)