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

Publication ,  Journal Article
Wang, M-T; Fer, N; Galeas, J; Collisson, EA; Kim, SE; Sharib, J; McCormick, F
Published in: Nature communications
July 2019

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.

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Published In

Nature communications

DOI

EISSN

2041-1723

ISSN

2041-1723

Publication Date

July 2019

Volume

10

Issue

1

Start / End Page

3055

Related Subject Headings

  • YAP-Signaling Proteins
  • Xenograft Model Antitumor Assays
  • Transcription Factors
  • Signal Transduction
  • RNA, Small Interfering
  • Proto-Oncogene Proteins p21(ras)
  • Phosphoproteins
  • Pancreatic Neoplasms
  • Mutation
  • Mice
 

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Wang, M.-T., Fer, N., Galeas, J., Collisson, E. A., Kim, S. E., Sharib, J., & McCormick, F. (2019). Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer. Nature Communications, 10(1), 3055. https://doi.org/10.1038/s41467-019-11044-9
Wang, Man-Tzu, Nicole Fer, Jacqueline Galeas, Eric A. Collisson, Sung Eun Kim, Jeremy Sharib, and Frank McCormick. “Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer.Nature Communications 10, no. 1 (July 2019): 3055. https://doi.org/10.1038/s41467-019-11044-9.
Wang M-T, Fer N, Galeas J, Collisson EA, Kim SE, Sharib J, et al. Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer. Nature communications. 2019 Jul;10(1):3055.
Wang, Man-Tzu, et al. “Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer.Nature Communications, vol. 10, no. 1, July 2019, p. 3055. Epmc, doi:10.1038/s41467-019-11044-9.
Wang M-T, Fer N, Galeas J, Collisson EA, Kim SE, Sharib J, McCormick F. Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer. Nature communications. 2019 Jul;10(1):3055.

Published In

Nature communications

DOI

EISSN

2041-1723

ISSN

2041-1723

Publication Date

July 2019

Volume

10

Issue

1

Start / End Page

3055

Related Subject Headings

  • YAP-Signaling Proteins
  • Xenograft Model Antitumor Assays
  • Transcription Factors
  • Signal Transduction
  • RNA, Small Interfering
  • Proto-Oncogene Proteins p21(ras)
  • Phosphoproteins
  • Pancreatic Neoplasms
  • Mutation
  • Mice