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

Man-Tzu Wang, Nicole Fer, Jacqueline Galeas, Eric A. Collisson, Sung Eun Kim, Jeremy Sharib and Frank McCormick ()
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Man-Tzu Wang: University of Pittsburgh
Nicole Fer: Frederick National Laboratory for Cancer Research
Jacqueline Galeas: University of California
Eric A. Collisson: University of California
Sung Eun Kim: University of California
Jeremy Sharib: University of California
Frank McCormick: University of California

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11044-9

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