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

Abstract

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.

• Authors: Man-Tzu Wang, Nicole Fer, Jacqueline Galeas, Eric A Collisson, Sung Eun Kim, Jeremy Sharib, Frank McCormick
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 3055 (07 11 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 31296870 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• IL6 protein, human
• Interleukin-6
• KRAS protein, human
• LIF protein, human
• Leukemia Inhibitory Factor
• Lif protein, mouse
• Phosphoproteins
• RNA, Small Interfering
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human
• Deoxycytidine
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)
• Gemcitabine

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Carcinoma, Pancreatic Ductal (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Deoxycytidine (analogs & derivatives, pharmacology, therapeutic use)
• Female
• Gene Knockout Techniques
• Humans
• Interleukin-6 (genetics, metabolism)
• Leukemia Inhibitory Factor (antagonists & inhibitors, genetics, metabolism)
• Mice
• Mutation
• Pancreatic Neoplasms (drug therapy, genetics, pathology)
• Phosphoproteins (genetics, metabolism)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Signal Transduction (genetics)
• Transcription Factors
• Xenograft Model Antitumor Assays
• YAP-Signaling Proteins
• Gemcitabine