An engineered ligand trap inhibits leukemia inhibitory factor as pancreatic cancer treatment strategy

Leukemia inhibitory factor (LIF), a cytokine secreted by stromal myofibroblasts and tumor cells, has recently been highlighted to promote tumor progression in pancreatic and other cancers through KRAS-driven cell signaling. We engineered a high affinity soluble human LIF receptor (LIFR) decoy that sequesters human LIF and inhibits its signaling as a therapeutic strategy. This engineered 'ligand trap', fused to an antibody Fc-domain, has similar to 50-fold increased affinity (similar to 20 pM) and improved LIF inhibition compared to wild-type LIFR-Fc, potently blocks LIF-mediated effects in pancreatic cancer cells, and slows the growth of pancreatic cancer xenograft tumors. These results, and the lack of apparent toxicity observed in animal models, further highlights ligand traps as a promising therapeutic strategy for cancer treatment. Hunter et al. engineer a high affinity, soluble variant of leukemia inhibitory factor receptor (LIFR) to serve as a ligand trap for the LIF cytokine. They further demonstrate that this engineered LIFR exhibits improved affinity relative to the wild-type receptor, leading to better disruption of LIF signaling in cancer cells, and highlighting promise of such ligand traps as therapeutic strategy for cancer treatment.

Automated summary

Hunter et al. engineered a high affinity, soluble variant of leukemia inhibitory factor receptor (LIFR) to serve as a ligand trap for the LIF cytokine. They demonstrated that this engineered LIFR exhibits improved affinity relative to the wild-type receptor, leading to better disruption of LIF signaling in cancer cells, and highlighting promise of such ligand traps as therapeutic strategy for cancer treatment.