Targeting cancer-associated fibroblast-mediated LIF/LIFR axis improves the therapeutic efficacy of gemcitabine and nab-paclitaxel in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) responds poorly to chemotherapeutics due to inherent drug resistance orchestrated by crosstalk between cancer cells and cancer-associated fibroblasts (CAFs). The LIF/LIFR axis activated by this crosstalk contributes significantly to cancer cell stemness and is a potential therapeutic target. Combined targeting of LIFR with small molecular inhibitors along with standard of care remains unexplored.The efficacy of LIFR small molecule inhibitor, EC359 was evaluated in combination with standard-of-care using human and mouse cell lines, tumoroids, KPC (KrasG12D; TP53R172H; Pdx1-Cre), and orthotopically co-implanted murine models. The impact of LIFR targeting on PDAC was analyzed by RNA-sequencing, immunohistochemistry, western blot, and immune profiles by flow cytometry.In co-implantation murine models, EC359 (5mg/kg body weight), in combination with gemcitabine (Gem, 25mg/kg body weight), reduced the tumor burdens up to 90% compared to the untreated controls (p<0.001) and by 55% compared to Gem alone. The RNA-seq analysis of treated tumors showed significant alterations in stemness markers, extracellular matrix modulation, microtubule structure assembly, and adaptive immune response, suggesting the simultaneous targeting of cell-intrinsic and TME-mediated mechanisms by EC359. The EC359 in autochthonous KPC tumors improved the efficacy of Gem and nab-paclitaxel targeting, increased the dendritic cells, but reduced regulatory T-cells, systemically. Mechanistically, EC359 reduces the PDAC cell stemness, stabilizes the microtubule assembly, and reduces the immunosuppressive microenvironment, contributing to improved efficacy of standard of care in PDAC.