Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31296870.
- Also identified by DOI 10.1038/s41467-019-11044-9 and PMC identifier 6624260.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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, Kras<sup>G12D</sup>-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.
Medical subject headings
- Antineoplastic Combined Chemotherapy Protocols
- Carcinoma, Pancreatic Ductal
- Leukemia Inhibitory Factor
- Pancreatic Neoplasms
- Proto-Oncogene Proteins p21(ras)