Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer.

Journal Article (Journal Article)

KRAS mutations are present in over 90% of pancreatic ductal adenocarcinomas (PDAC), and drive their poor outcomes and failure to respond to targeted therapies. Here we show that Leukemia Inhibitory Factor (LIF) expression is induced specifically by oncogenic KRAS in PDAC and that LIF depletion by genetic means or by neutralizing antibodies prevents engraftment in pancreatic xenograft models. Moreover, LIF-neutralizing antibodies synergize with gemcitabine to eradicate established pancreatic tumors in a syngeneic, KrasG12D -driven, PDAC mouse model. The related cytokine IL-6 cannot substitute for LIF, suggesting that LIF mediates KRAS-driven malignancies through a non-STAT-signaling pathway. Unlike IL-6, LIF inhibits the activity of the Hippo-signaling pathway in PDACs. Depletion of YAP inhibits the function of LIF in human PDAC cells. Our data suggest a crucial role of LIF in KRAS-driven pancreatic cancer and that blockade of LIF by neutralizing antibodies represents an attractive approach to improving therapeutic outcomes.

Full Text

Duke Authors

Cited Authors

  • Wang, M-T; Fer, N; Galeas, J; Collisson, EA; Kim, SE; Sharib, J; McCormick, F

Published Date

  • July 11, 2019

Published In

Volume / Issue

  • 10 / 1

Start / End Page

  • 3055 -

PubMed ID

  • 31296870

Pubmed Central ID

  • PMC6624260

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

International Standard Serial Number (ISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-019-11044-9

Language

  • eng