Targeting cancer-associated fibroblast-driven LIF/LIFR axis improves the therapeutic efficacy of gemcitabine and nab-paclitaxel in pancreatic cancer
Year: 2025
Type: article
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is inherently therapy resistant due to cancer cell-stroma crosstalk across several signaling pathways. Among these, the LIF/LIFR axis has been implicated in cancer cell and cancer-associated fibroblast (CAF) crosstalk. We evaluated the efficacy of EC359, a competitive inhibitor of LIFR, in combination with gemcitabine. EC359 reduced tumor burden by 90% compared to controls and by 55% compared to gemcitabine alone in cancer cell and CAFs co-implannation model. The RNA-seq analysis revealed a significant alteration in extracellular matrix components, stemness, microtubule assembly, and immune response, suggesting simultaneous targeting of cancer cell-intrinsic and stroma-mediated mechanisms by EC359. In autochthonous murine model of PDAC, EC359 enhanced the therapeutic efficacy of gemcitabine and nab-paclitaxel, accompanied by an increase in dendritic cells but a reduction in T-regulatory cells. Thus, EC359 reduces PDAC cell stemness, stabilizes microtubule assembly, and reduces the immunosuppressive microenvironment to improve the efficacy of standard-of-care in PDAC.
Source: npj Precision Oncology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,090
Awards: G1199706347, Targeting LIF/LIFR in pancreatic cancer, G3276303307, G377846833, G4642690177, Rac1 GTPase in tumorigenesis and progression of pancreatic cancer, G6263938444, Pancreatic Cancer Metastasis, G894044079, G9000014151, G9000032122, G9000067163, G9000067508, G9000126677, G9000129900, G9000130102, G9000147310, G9000171213, G9000295445, G9000341061, Lysosome Trapped FAP-Targeted Theranostics for Pancreatic Cancer
OpenAlex ID: W4413438090